Cyclic benizimidazoles

ABSTRACT

The invention relates to cyclic benzimidazoles of formula 1,  
                 
in which the substituents and symbols have the meanings indicated in the description. The compounds have gastric secretion inhibiting and excellent gastric and intestinal protective action properties.

TECHNICAL FIELD

The invention relates to novel compounds, which are used in thepharmaceutical industry as active compounds for the production ofmedicaments.

Prior Art

In European patent application 266326 (which corresponds to U.S. Pat.No. 5,106,862), benzimidazole derivatives having a very broad variety ofsubstituents are disclosed, which are said to be active as anti-ulceragents. In J. Med. Chem. 1991, 34, 533-541 (Kaminski et al.), theinhibition of gastric H⁺/K⁺-ATPase by certain substitutedimidazo[1,2-a]pyridines is described. Kaminski et al. describe in alater publication (J. Med. Chem. 1997, 40, 427-436) the results of adetailed analysis of the same and similar imidazo[1,2-a]pyridines.Tricyclic imidazo[1,2-a]pyridines with a specific substitution patternare described in the International Patent Application WO 95/27714 (AstraAB). In the international Patent Application WO 03/014123 (ALTANA PharmaAG), new imidazo[1,2-]pyridines with a certain substitution pattern aredisclosed. In the International Patent Application WO 97/47603 (AstraAB) benzimidazoles with a specific benzyloxy or benzylamino substitutionare described.

SUMMARY OF THE INVENTION

The invention relates to condensed benzimidazoles of the formula 1

in which

-   -   R₁ is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl,        3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,        1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl,        fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or        di-1-4C-alkylamino,    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,        aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,        1-4C-alkoxycarbonyl, mono- or        di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl,        fluoro-2-4C-alkyl,    -   R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,        1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy,        1-4C-alkylcarbonylamino, 1-4C-alkylcarbonyl-N-1-4-alkylamino,        1-4C-alkoxy-1-4C-alkylcarbonylamino or the group —CO—NR31R32,        where    -    R31 is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl,        hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl,        hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolicino, hydroxy-pyrrolidino, aziridino,        azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or        morpholino group,    -   X is O (oxygen) or NH and    -   Ar is a mono- or bicyclic aromatic residue, substituted by R4,        R5, R6 and R7, which is selected from the group consisting of        phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,        1,2,3-trazolyl, indolyl, benzimidazolyl, furyl, benzofuryl,        thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl,        pyrmidinyl, chinolinyl and isochinolinyl, wherein    -    R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy,        1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,        1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl,        aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl,        nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sufonyl,    -    R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxy,    -    R6 is hydrogen, 1-4C-alkyl or halogen and    -    R7 is hydrogen, 1-4C-alkyl or halogen, and wherein    -    aryl is phenyl or substituted phenyl with one, two or three        same or different substituents from the group of 1-4C-alkyl,        1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano,    -   and the salts of these compounds.

Halogen within the meaning of the invention is bromo, chloro and fluoro.

1-4C-Alkyl represents a straight chain or branched alkyl group having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methylgroup.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned1-4C-alkyl groups, which is substituted by one of the aforementioned3-7C-cycloalkyl groups. Examples which may be mentioned are thecyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.

1-4C-Alkoxy represents a group, which in addition to the oxygen atomcontains one of the aforementioned 1-4C-alkyl groups. Examples which maybe mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy,propoxy, isopropoxy and preferably the ethoxy and methoxy group.

1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkylgroups, which is substituted by one of the aforementioned 1-4C-alkoxygroups. Examples which may be mentioned are the methoxymethyl, themethoxyethyl group and the butoxyethyl group.

1-4C-Alkoxycarbonyl (1-4C-alkoxy-CO—) represents a carbonyl group, towhich one of the aforementioned 1-4C-alkoxy groups is bonded. Exampleswhich may be mentioned are the methoxycarbonyl (CH₃O—C(O)—) and theethoxycarbonyl group (CH₂CH₂O—C(O)—).

2-4C-Alkenyl represents a straight-chain or branched alkenyl grouphaving 2 to 4 carbon atoms. Examples which may be mentioned are the2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).

2-4C-Alkynyl represents a straighten or branched alkynyl group having 2to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl,3-butynyl, and preferably the 2-propynyl, group (propargyl group).

Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkylgroups, which is substituted by one or more fluorine atoms. An examplewhich may be mentioned is the trifluoromethyl group.

Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkylgroups, which is substituted by a hydroxy group. Examples which may bementioned are the hydroxymethyl, the 2-hydroxyethyl and the3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of theinvention is understood to include 1-4C-alkyl groups with two or morehydroxy groups. Examples which may be mentioned are the3,4-dihydroxybutyl and in particular the 2,3-dyhdroxypropyl group.

Mono- or di-1-4C-alkylamino represents an amino group, which issubstituted by one or by two—identical or different—groups from theaforementioned 1-4C-alkyl groups. Examples which may be mentioned arethe dimethylamino, the diethylamino and the diisopropylamino group.

Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a1-4C-alkylcarbonyl group, which is substituted by a mono- or1-4C-alkylamino groups. Examples, which may be mentioned, are thedimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.

Fluoro-2-4C-alkyl represents a 2-4C-alkyl group, which is substituted byone or more fluorine atoms. An example which may be mentioned is the2,2,2-trifluoroethyl group.

1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxygroups, which is substituted by a further 1-4C-alkoxy group. Exampleswhich may be mentioned are the groups 2-(methoxy)ethoxy (CH₃O—CH₂—O—)and 2-(ethoxy)ethoxy (CH₃—CH₂—O—CH₂CH₂—O—).

1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of theaforementioned 1-4C-alkoxy groups. An example which may be mentioned isthe group 2-methoxy)ethoxymethyl (CH₃—O—CH₂—CH₂—O—CH₂).

Fluoro-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxygroups, which is completely or mainly substituted by fluorine, “mainly”meaning in this connection that more than half of the hydrogen atoms arereplaced by fluorine atoms. Examples of completely or mainlyfluoro-substituted 1-4C-alkoxy groups which may be mentioned are the1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably thedifluoromethoxy group.

Fluoro-1 -4C-alkoxy-1-4C-alkyl represents one of the aforementioned1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group.Examples of fluoro-1-4C-alkoxy-1-4C-alkyl groups are the1,1,2,2-tetrafluoroethoxymethyl, the 2,2,24-trifluoroethoxymethyl, thetrifluoromethoxyethyl and the difluoromethoxyethyl group.

1-7C-Alkyl represents a straight-chain or branched alkyl group having 1to 7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl(3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and the methyl group.

Groups Ar which may be mentioned are, for example, the followingsubstituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl,3,5-bis(trifluoromethyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-chloro-6-fluorophenyl,3-chloro-fluorophenyl, 2-chloro-5-nitrophenyl, 4chloro-3-nitrophenyl,3-4chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,2,4-dihydroxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyl,2,5-dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl,4-fluorophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl,3-methoxy-2-nitrophenyl, 3-nitrophenyl, 2,3,5-trichlorophenyl,2,4,6-trihydroxyphenyl, 2,3,4-trimethoxyphenyl, 2-hydroxy-1-naphthyl,2-methoxy-1-naphthyl, 4-methoxy-1-naphthyl, 1-methyl-2-pyrrolyl,2-pyrrolyl, 3-methyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl,4-(2-methoxycarbonylethyl)-3-methyl-2-pyrrolyl,5-ethoxycarbonyl-2,4-dimethyl-3-pyrrolyl, 3,4dibromo-5-ethyl-2-pyrrolyl,2,5-dimethyl-1-phenyl-3pyrrolyl, 5-carboxy-3-ethyl-4-methyl-2-pyrrolyl,3,5-dimethyl-2-pyrrolyl,2,5-dimethyl-1-(4-trifluoromethylphenyl)-3-pyrrolyl,1-(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl,1-(2-nitrobenzyl)-2-pyrrolyl. 1(2-fluorophenyl)-2-pyrrolyl,1-(4-trifluoromethoxyphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl,1-(4-ethoxycarbonyl)-2,5-dimethyl-3pyrrolyl,5-chloro-1,3-dimethyl-4-pyrazolyl,5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl,1-(4-chlorobenzyl)-5-pyrazolyl,1,3-dimethyl-5-(4-chlorphenoxy)-4-pyrazolyl,1-methyl-3-trifluomethyl-5-(3-trifluoromethylphenoxy)-4-pyrazolyl,4-methoxycarbonyl-1-(2,6dichlorophenyl)-5-pyrazolyl,5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl,5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl,3,5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl,2-butylimidazolyl, 1-phenyl-1,2,3-triazol-4-yl, 3-indolyl, 4-indolyl,7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl,1-benzyl-3-indolyl, 2-(4-chlorophenyl)-3-indolyl, 7-benzyloxy-indolyl,6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl,4,5,6,7-tetrafluoro-3-indolyl, 1(3,5-difluorobenzyl)-3-indolyl,1-methyl-2-(4-trifluorophenoxy)-3-indolyl, 1-methyl-2-benzimidazolyl,5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl,5(2-nitro-4-trifluoromethylphenyl)-2-furyl,4-ethoxycarbonyl5-methyl-2-furyl, 5-(2-trifluoromethoxyphenyl)-2-furyl,5(4-methoxy-2-nitrophenyl)-2-furyl, 4-bromo-2-furyl,5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuryl,2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl,5-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl,5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl,5-carboxy-2-thienyl, 2,5-dichloro-3-thienyl, 3-methoxy-2-thienyl,2-benzothienyl, 3-methyl-2-benzothienyl,2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl,2-amino-4-chloro-5-thiazolyl, 2,4-dichloro-5-thiazolyl,2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl,3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2,6-dichloro-4-pyridyl,3-chloro-5-trifluoromethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl,4(4-chlorophenyl)-pyridyl,2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl,2-chloro-3pyridyl, 6(3-trifluoromethyl)phenoxy)-3-pyridyl,2-(4-chlorophenoxy-3-pyridyl, 2,4-dimethoxy-5-pyrimidinyl, 2-quinolinyl,3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl,2-chloro-6-methoxy-3-quinolinyl, 8-hydroxy-2-quinolinyl and4-isoquinolinyl.

2-4C-Alkenyloxy represents a group, which in addition to the oxygen atomcontains one of the above-mentioned 2-4C-alkenyl groups. Examples, whichmay be mentioned, are the 2-butenyloxy, 3-butenyloxy, 1-propenyloxy andthe 2-propenyloxy group (allyloxy group).

1-4C-Alkylcarbonyl represents a group, which in addition to the carbonylgroup contains one of the abovementioned 1-4C-alkyl groups. An examplewhich may be mentioned is the acetyl group.

Carboxy-1-4C-alkyl represents a 1-4C-alkyl group which is substituted bya carboxyl group. Examples, which may be mentioned, are thecarboxymethyl and the 2-carboxyethyl group.

1-4C-Alkoxycarbonyl-1-4C-alkyl represents a 1-4C-alkyl group, which issubstituted by one of the abovementioned 1-4C-alkoxycarbonyl groups.Examples, which may be mentioned, are the Methoxy-carbonylmethyl and theethoxycarbonylmethyl group.

Aryl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups,which is substituted by one of the abovementioned aryl groups. Anexemplary preferred aryl-1-4C-alkyl group is the benzyl group.

Aryl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxygroups, which is substituted by one of the abovementioned aryl groups.An exemplary preferred aryl-1-4C-alkoxy group is the benzyloxy group.

1-4C-Alkylcarbonylamino represents an amino group to which a1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned arethe proplonylamino (C₃H₇C(O)NH—) and the acetylamino group (acetamidogroup) (CH₃C(O)NH—).

1-4C-Alkoxycarbonylamino represents an amino group, which is substitutedby one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, whichmay be mentioned, are the ethoxycarbonylamino and themethoxycarbonylamino group.

1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to whichone of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded.Examples which may be mentioned are the 2-(methoxy)ethoxy-carbonyl(CH₃—O—CH₂CH₂—O—CO—) and the 2-(ethoxy)ethoxycarbonyl group(CH₃CH₂—O—CH₂CH₂—O—CO—).

1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which issubstituted by one of the aforementioned 1-4alkoxy-1-4C-alkoxycarbonylgroups. Examples which may be mentioned are the2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylaminogroup.

Possible salts of compounds of the formula 1—depending onsubstitution—are especially all acid addition salts. Particular mentionmay be made of the pharmacologically tolerable salts of the inorganicand organic acids customarily used in pharmacy. Those suitable arewater-soluble and water-insoluble acid addition salts with acids suchas, for example, hydrochloric acid, hydrobromic acid, phosphoric acid,nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid,benzoic acid, 2-(4hydroxybenzoyl)-benzoic acid, butyric acid,sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid,toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoicacid, where the acids are used in salt preparation—depending on whethera mono- or polybasic acid is concerned and on which salt is desired—inan equimolar quantitative ratio or one differing therefrom.

Pharmacologically intolerable salts, which can initially be obtained,for example, as process products in the production of the compoundsaccording to the invention on the industrial scale, are converted intothe pharmacologically tolerable salts by processes known to the personskilled in the art.

It is known to the person skilled in the art that the compoundsaccording to invention and their salts, if, for example, they areisolated in crystalline form, can contain various amounts of solvents.The invention therefore also comprises all solvates and in particularall hydrates of the compounds of the formula 1, and also all solvatesand in particular all hydrates of the salts of the compounds of theformula 1.

The compounds of the formula 1 have a chirality center in the8-position. The invention thus relates to both enantomers in any desiredmixing ratio to another, including the pure enantiomers, which are apreferred subject of the invention.

One aspect of the invention are compounds of formula 1, in which R3 is1-4C-alkylcarbonyl-N-1-4C-alkylamino and R1, R2, X and Ar have themeanings given above, and the salts of these compounds.

Another aspect of the invention are compounds of formula 1, in which R3is the group —CO—NR31R32 in which R31 and R32 together, including thenitrogen atom to which both are bonded, are a hydroxy-pyrrolidino groupand R1, R2, X and Ar have the meanings given above, and the salts ofthese compounds.

Yet another aspect of the invention are compounds of formula 1, in whichR3 is the group —CO—NR31R32 in which R31 and R32 together, including thenitrogen atom to which both are bonded, are an aziridino group and R1,R2, X and Ar have the meanings given above, and the salts of thesecompounds.

Yet another aspect of the invention are compounds of formula 1, in whichR3 is the group —CO—NR31R32 in which R31 and R32 together, including thenitrogen atom to which both are bonded, are an azetidino group and R1,R2, X and Ar have the meanings given above, and the salts of thesecompounds.

One embodiment (embodiment a) of the invention are compounds of formula1, in which

-   -   R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl,        3-7-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,        1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl,        fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or        di-1-4C-alkylamino,    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,        aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,        1-4C-alkoxycarbonyl, mono- or        di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl,        fluoro-2-4C-alkyl,

R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or thegroup —CO—NR31R32, where

-   -    R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl,        hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, piperidino, piperazino,        N-1-4C-alkylpiperazino or morpholino group,    -   X is O (oxygen) or NH and    -   Ar is a mono- or bicyclic aromatic residue, substituted by R4,        R5, R6 and R7, which is selected from the group consisting of        phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,        1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl,        thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl,        pyrimidinyl, chinolinyl and isochnolinyl, wherein    -    R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 14C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy,        1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,        1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl,        aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl,        nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -    R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxy,    -    R6 is hydrogen, 1-4C-alkyl or halogen and    -    R7 is hydrogen, 1-4C-alkyl or halogen, and wherein    -    aryl is phenyl or substituted phenyl with one, two or three        same or different substituents from the group of 1-4C-alkyl,        1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,        trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano,    -   and the salts of these compounds.

Compounds to be mentioned particularly are those of formula 1, in which

-   -   R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or        fluoro-1-4C-alkyl,    -   R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is hydrogen, halogen, carboxyl, 1-4C-alkoxycarbonyl,        hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,        1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32        where    -    R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,        hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino,        azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or        morpholino group,    -   X is O (oxygen) or NH and    -   Ar is a phenyl group, substituted by R4, R5, R6 and R7, wherein    -    R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy,        1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,        1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -    R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxy,    -    R6 is hydrogen, 1-4C-alkyl or halogen and    -    R7 is hydrogen, 1-4C-alkyl or halogen,    -   and the salts of these compounds.

Among the compounds of formula 1, those of the formula 1 a are preferred

in which

-   -   R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or        fluoro-1-4C-alkyl,    -   R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is hydrogen, halogen, carboxyl, 1-4C-alkoxycarbonyl,        hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,        1-4C-alkylcarbonyl-1-4C-alkylamino or the group —CO—NR31R32,        where    -    R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,        hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino,        azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or        morpholino group,    -   R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or        di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,        1-4C-alkoxycarbonylamino or        1-4C-alkoxy-1-4C-alkoxycarbonylamino,    -   R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Among the compounds of formula 1, those of the formula 1a areparticularly preferred in which

-   -   R1 is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,    -   R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is hydrogen, carboxyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,        1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32,        where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, aziridino, azetidino or        morpholino group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Exemplified compounds to be mentioned particularly are those of formula1a, in which

-   -   R1 is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,    -   R2 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,        1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32,        where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino,        azetidino or morpholino group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Compounds of embodiment a to be mentioned particularly are those offormula 1, in which

-   -   R1 is hydrogen or 1-4C-alkyl,    -   R2 is hydrogen or 1-4C-alkyl,    -   R3 is halogen, carboxyl, 1-4C-alkoxycarbonyl,        hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or the group        —CO—NR31R32, where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, piperidino, piperazino,        N-1-4C-alkylpiperazino or morpholino group,    -   X is O (oxygen) or NH and    -   Ar is a phenyl group, substituted by R4, R5, R6 and R7, wherein    -    R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy,        1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,        1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy,        trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,        1-4-C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,        1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,    -    R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl,        halogen, trifluoromethyl or hydroxy,    -    R6 is hydrogen, 1-4C-alkyl or halogen and    -    R7 is hydrogen, 1-4C-alkyl or halogen,    -   and the salts of these compounds.

Among the compounds of formula 1 of embodiment a, those of the formula1a are preferred, in which

-   -   R1 is hydrogen or 1-4C-alkyl,    -   R2 is hydrogen or 1-4C-alkyl,    -   R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl or the group —CO—NR31R32, where    -    R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-7C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, piperidino, piperazino,        N1-4C-alkylpiperazino or morpholino group,    -   R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,        1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or        di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,        1-4C-alkoxycarbonylamino or        1-4C-alkoxy-1-4C-alkoxycarbonylamino,    -   R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Among the compounds of formula 1 of embodiment a, those of the formula1a are particularly preferred in which

-   -   R1 is 1-4C-alkyl,    -   R2 is 1-4C-alkyl,    -   R3 is hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or the group        —CO—NR31R32, where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or        1-4C-alkoxy-2-4C-alkyl and    -    R32 is hydrogen, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Among the compounds of formula 1 of embodiment a, those exemplifiedcompounds of the formula 1a are particularly preferred in which

-   -   R1 is 1-4C-alkyl or fluoro-1-4C-alkyl,    -   R2 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or        the group —CO—NR31R32, where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or        1-4C-alkoxy-2-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino or morpholino group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Preferred subject of the invention are compounds of the formula 2

in which

-   -   R1 is 1-4C-alkyl or 3-7C-cycloalkyl,    -   R2 is hydrogen or 1-4C-alkyl,    -   R3 is 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl or the group —CO—NR31R32, where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, aziridino, azetidino or        morpholino group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Preferred exemplified compounds of the invention are those of formula 2,in which

-   -   R1 is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl,    -   R2 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,    -   R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,        1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,        1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32,        where    -    R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or        1-4C-alkoxy-1-4C-alkyl and    -    R32 is hydrogen or 1-4C-alkyl, or where    -    R31 and R32 together, including the nitrogen atom to which both        are bonded, are a pyrrolidino, hydroxypyrrolidino, aziridino,        azetidino or morpholino group,    -   R4 is hydrogen,    -   R5 is hydrogen and    -   X is O (oxygen) or NH,    -   and the salts of these compounds.

Exemplary preferred compounds are those of the formula 1a, in which R1,R2, R3, R4, R5 and X have the meanings given in the following table 1(Me=CH₃, Et=C₂H₅), and the salts of these compounds.

Exemplary particularly preferred compounds are those of the formula 2,in which R1, R2, R3, R4, R5 and X have the meanings given in thefollowing table 1 (Me=CH₃, Et=C₂H₅), and the salts of these compounds.TABLE 1 R1 R2 R3 R4 R5 X Me Me CH₂OH H H O Me Me CH₂OCH₃ H H O Me MeCONHMe H H O Me Me CON-pyrrolidine H H O Me Me CONH(CH₂)₂OH H H O Me MeCONH(CH₂)₂OMe H H O Me Me CONH₂ H H O Me Me CON-morpholine H H O Me MeCONMe₂ H H O Me Me CH₂O(CH₂)₂OMe H H O Me Me CON-aziridine H H O Me MeCOOEt H H O Me Me COOH H H O Me Me CON-azetidine H H O Me MeCONH(CH₂)₂Me H H O Me Me CONHCH₂CHOHCH₂OH H H O Me Me NCH₃COCH₃ H H O MeMe NHCOCH₃ H H O Me Me NHCOCH₂OMe H H O Me Me NHCO(CH₂)₂OMe H H O Me MeOCH₂OMe H H O Me Me O(CH₂)₂OMe H H O Me Me CONH-cyclopropyl H H O Me MeH H H O Cyclopropyl Me CH₂OCH₃ H H O Cyclopropyl Me CONHMe H H OCyclopropyl Me CON-pyrrolidine H H O Cyclopropyl Me CONH(CH₂)₂OH H H OCyclopropyl Me CONH(CH₂)₂OMe H H O Cyclopropyl Me CONH₂ H H OCyclopropyl Me CON-morpholine H H O Cyclopropyl Me CONMe₂ H H OCyclopropyl Me CH₂O(CH₂)₂OMe H H O Cyclopropyl Me CON-aziridine H H OCyclopropyl Me COOEt H H O Cyclopropyl Me COOH H H O Cyclopropyl MeCON-azetidine H H O Cyclopropyl Me CONH(CH₂)₂Me H H O Cyclopropyl MeCONHCH₂CHOHCH₂OH H H O Cyclopropyl Me NCH₃COCH₃ H H O Cyclopropyl MeNHCOCH₃ H H O Cyclopropyl Me NHCOCH₂OMe H H O Cyclopropyl MeNHCO(CH₂)₂OMe H H O Cyclopropyl Me OCH₂OMe H H O Cyclopropyl MeO(CH₂)₂OMe H H O Cyclopropyl Me CONH-cyclopropyl H H O Cyclopropyl Me HH H O CF₃ Me CH₂OCH₃ H H O CF₃ Me CONHMe H H O CF₃ Me CON-pyrrolidine HH O CF₃ Me CONH(CH₂)₂OH H H O CF₃ Me CONH(CH₂)₂OMe H H O CF₃ Me CONH₂ HH O CF₃ Me CON-morpholine H H O CF₃ Me CONMe₂ H H O CF₃ Me CH₂O(CH₂)₂OMeH H O CF₃ Me CON-aziridine H H O CF₃ Me COOEt H H O CF₃ Me COOH H H OCF₃ Me CON-azetidine H H O CF₃ Me CONH(CH₂)₂Me H H O CF₃ MeCONHCH₂CHOHCH₂OH H H O CF₃ Me NCH₃COCH₃ H H O CF₃ Me NHCOCH₃ H H O CF₃Me NHCOCH₂OMe H H O CF₃ Me NHCO(CH₂)₂OMe H H O CF₃ Me OCH₂OMe H H O CF₃Me O(CH₂)₂OMe H H O CF₃ Me CONH-cyclopropyl H H O CF₃ Me H H H O MeCH₂OMe CH₂OCH₃ H H O Me CH₂OMe CONHMe H H O Me CH₂OMe CON-pyrrolidine HH O Me CH₂OMe CONH(CH₂)₂OH H H O Me CH₂OMe CONH(CH₂)₂OMe H H O Me CH₂OMeCONH₂ H H O Me CH₂OMe CON-morpholine H H O Me CH₂OMe CONMe₂ H H O MeCH₂OMe CH₂O(CH₂)₂OMe H H O Me CH₂OMe CON-aziridine H H O Me CH₂OMe COOEtH H O Me CH₂OMe COOH H H O Me CH₂OMe CON-azetidine H H O Me CH₂OMeCONH(CH₂)₂Me H H O Me CH₂OMe CONHCH₂CHOHCH₂OH H H O Me CH₂OMe NCH₃COCH₃H H O Me CH₂OMe NHCOCH₃ H H O Me CH₂OMe NHCOCH₂OMe H H O Me CH₂OMeNHCO(CH₂)₂OMe H H O Me CH₂OMe OCH₂OMe H H O Me CH₂OMe O(CH₂)₂OMe H H OMe CH₂OMe CONH-cyclopropyl H H O Me CH₂OMe H H H O Me H CH₂OCH₃ H H O MeH CONHMe H H O Me H CON-pyrrolidine H H O Me H CONH(CH₂)₂OH H H O Me HCONH(CH₂)₂OMe H H O Me H CONH₂ H H O Me H CON-morpholine H H O Me HCONMe₂ H H O Me H CH₂O(CH₂)₂OMe H H O Me H CON-aziridine H H O Me HCOOEt H H O Me H COOH H H O Me H CON-azetidine H H O Me H CONH(CH₂)₂Me HH O Me H CONHCH₂CHOHCH₂OH H H O Me H NCH₃COCH₃ H H O Me H NHCOCH₃ H H OMe H NHCOCH₂OMe H H O Me H NHCO(CH₂)₂OMe H H O Me H OCH₂OMe H H O Me HO(CH₂)₂OMe H H O Me H CONH-cyclopropyl H H O Me H H H H O Me Me H H H NHCyclopropyl Me CH₂OCH₃ H H NH Cyclopropyl Me CONHMe H H NH CyclopropylMe CON-pyrrolidine H H NH Cyclopropyl Me CONH(CH₂)₂OH H H NH CyclopropylMe CONH(CH₂)₂OMe H H NH Cyclopropyl Me CONH₂ H H NH Cyclopropyl MeCON-morpholine H H NH Cyclopropyl Me CONMe₂ H H NH Cyclopropyl MeCH₂O(CH₂)₂OMe H H NH Cyclopropyl Me CON-aziridine H H NH Cyclopropyl MeCOOEt H H NH Cyclopropyl Me COOH H H NH Cyclopropyl Me CON-azetidine H HNH Cyclopropyl Me CONH(CH₂)₂Me H H NH Cyclopropyl Me CONHCH₂CHOHCH₂OH HH NH Cyclopropyl Me NCH₃COCH₃ H H NH Cyclopropyl Me NHCOCH₃ H H NHCyclopropyl Me NHCOCH₂OMe H H NH Cyclopropyl Me NHCO(CH₂)₂OMe H H NHCyclopropyl Me OCH₂OMe H H NH Cyclopropyl Me O(CH₂)₂OMe H H NHCyclopropyl Me CONH-cyclopropyl H H NH Cyclopropyl Me H H H NH CF₃ MeCH₂OCH₃ H H NH CF₃ Me CONHMe H H NH CF₃ Me CON-pyrrolidine H H NH CF₃ MeCONH(CH₂)₂OH H H NH CF₃ Me CONH(CH₂)₂OMe H H NH CF₃ Me CONH₂ H H NH CF₃Me CON-morpholine H H NH CF₃ Me CONMe₂ H H NH CF₃ Me CH₂O(CH₂)₂OMe H HNH CF₃ Me CON-aziridine H H NH CF₃ Me COOEt H H NH CF₃ Me COOH H H NHCF₃ Me CON-azetidine H H NH CF₃ Me CONH(CH₂)₂Me H H NH CF₃ MeCONHCH₂CHOHCH₂OH H H NH CF₃ Me NCH₃COCH₃ H H NH CF₃ Me NHCOCH₃ H H NHCF₃ Me NHCOCH₂OMe H H NH CF₃ Me NHCO(CH₂)₂OMe H H NH CF₃ Me OCH₂OMe H HNH CF₃ Me O(CH₂)₂OMe H H NH CF₃ Me CONH-cyclopropyl H H NH CF₃ Me H H HNH Me CH₂OMe CH₂OCH₃ H H NH Me CH₂OMe CONHMe H H NH Me CH₂OMeCON-pyrrolidine H H NH Me CH₂OMe CONH(CH₂)₂OH H H NH Me CH₂OMeCONH(CH₂)₂OMe H H NH Me CH₂OMe CONH₂ H H NH Me CH₂OMe CON-morpholine H HNH Me CH₂OMe CONMe₂ H H NH Me CH₂OMe CH₂O(CH₂)₂OMe H H NH Me CH₂OMeCON-aziridine H H NH Me CH₂OMe COOEt H H NH Me CH₂OMe COOH H H NH MeCH₂OMe CON-azetidine H H NH Me CH₂OMe CONH(CH₂)₂Me H H NH Me CH₂OMeCONHCH₂CHOHCH₂OH H H NH Me CH₂OMe NCH₃COCH₃ H H NH Me CH₂OMe NHCOCH₃ H HNH Me CH₂OMe NHCOCH₂OMe H H NH Me CH₂OMe NHCO(CH₂)₂OMe H H NH Me CH₂OMeOCH₂OMe H H NH Me CH₂OMe O(CH₂)₂OMe H H NH Me CH₂OMe CONH-cyclopropyl HH NH Me CH₂OMe H H H NH Me H CH₂OCH₃ H H NH Me H CONHMe H H NH Me HCON-pyrrolidine H H NH Me H CONH(CH₂)₂OH H H NH Me H CONH(CH₂)₂OMe H HNH Me H CONH₂ H H NH Me H CON-morpholine H H NH Me H CONMe₂ H H NH Me HCH₂O(CH₂)₂OMe H H NH Me H CON-aziridine H H NH Me H COOEt H H NH Me HCOOH H H NH Me H CON-azetidine H H NH Me H CONH(CH₂)₂Me H H NH Me HCONHCH₂CHOHCH₂OH H H NH Me H NCH₃COCH₃ H H NH Me H NHCOCH₃ H H NH Me HNHCOCH₂OMe H H NH Me H NHCO(CH₂)₂OMe H H NH Me H OCH₂OMe H H NH Me HO(CH₂)₂OMe H H NH Me H CONH-cyclopropyl H H NH Me H H H H NH

Particularly preferred are the compounds given as final products offormula 1 in the examples, and the salts of these compounds.

The compounds according to the invention can be synthesised fromcorresponding starting compounds, for example according to the reactionschemes given below (scheme 1, scheme 2 and scheme 3). The synthesis iscarried out in a manner known to the expert, for example as described inmore detail in the examples which follow the schemes.

The starting compounds are known, for example, from Gillespie et al., J.Org. Chem. 1960, 25 942 (6-chloro-2-methyl-4-nitro-1(3)H-benzimidazole,J. R. E. Hoover, A. R. Day, J. Amer. Chem. Soc. 1955, 77, 4324(4-nitro-1(3)H-benzimidazole-6-carboxamide) or A R. Katritzky et al.,Heterocycles 1995, 41, 345-452 (4-hydroxy-1-methyl-1H-benzimidazole) orthey can be prepared using analogous process steps.

The preparation of the compounds of formula 1 where X═O [scheme 1,compounds (5)] can be carried out in a manner known to the personskilled in the art, for example, analogously as described in more detailin International Patent Applications WO 95/27714 and WO 03/014123.

Compounds of the formula 1 where X═NH [scheme 2, compounds (7)] can beobtained according to scheme 2, starting from corresponding substituted4aminobenzimidazoles known from literature.

The derivatzation, if any, of the compounds obtained according to theabove Schemes 1 and 2 (e.g. conversion of a group R3 into another groupR3, or of R2=H into another group e. g. R2=1-4C-alkyl) is likewisecarried out in a manner known to the expert. If compounds whereR3=—CO-1-4C-alkoxy or R3=—CO—NR31R32 are desired, an appropriatederivatization can be performed in a manner known to the expert (e.g.metal catalysed carbonylation of the corresponding halo compound orconversion of an ester into an amide) at the stage of the benzimidazolesof formula 3 or 5 (schemes 1 and 2) or more conveniently at a laterpoint in time.

The compounds of the formula 2 can be isolated from the correspondingracemic mixtures of the formula 1 by techniques known to the expert. Theseparation can be achieved for example by preparative chromatographyusing a chiral column, as described in an exemplary manner in theexamples.

Alternatively compounds of the formula 2 where X═O, with any desiredsubstituent R1, R2, R3 and Ar can be prepared in a stereoselective wayfollowing the reaction steps as outlined generally in scheme 3.Compounds of the formula 8 can be obtained from compounds of the formula4 by an asymmetric hydrogenation using a chiral hydrogenation catalystlike for example Ruthenium catalysts as described by Noyori et al. inAngew. Chem. 2001,113, 40-75.

Compounds of the formula 4 are known for example from WO 03/014123, orthey can be prepared in a known manner, analogously to known compounds.

The following examples serve to illustrate the invention in greaterdetail without restricting it. Likewise, further compounds of theformula 1 or 2 whose preparation is not described explicitly can beprepared in an analogous manner or in a manner familiar per se to theperson skilled in the art using customary process techniques. Theabbreviation min stands for minute(s), h for hour(s).

EXAMPLES

Final Products of Formula (1)

1.2,3-Dimethyl-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-a]imidazole-5-carboxylicAcid Dimethylamide

10 ml Phosphoric acid (85%) were heated to 80° C. for 10 min and then850 mg (2.3 mmol)7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzimidazole-5-carboxylicacid dimethylamide were added during 10 min. After heating at 80° C. for1 h, the reaction mixture was poured into ice-water (20 ml) andneutralized with 2M sodium hydroxide solution. The precipitate wasfiltered off and crystallized from ethyl acetate to give 555 mg (68%) ofthe title compound as a white solid. m. p. 236°-237° C.

2.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicAcid Dimethylamide

To a solution of 1.5 g (4.2 mmol)5-bromo-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinolinein 60 ml dimethylamine (5M solution in tetrahydrofuran) were added 95 mg(0.42 mmol) palladium(II) acetate and 0.66 g (2.5 mmol)triphenylphosphine. The mixture was transferred to an autoclave andcarbonylated (6 bar carbon monoxide pressure, 120° C.) for 18 h. Thereaction mixture was cooled down, poured into a mixture of saturatedammonium chloride solution (200 ml) and water (100 ml). The mixture wasextracted with dichloromethane, the organic layer washed with water,dried over anhydrous magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica gel(toluene/dioxane/methanol=6:3.5:0.5). Crystallization from ethyl acetateyielded 0.43 g (29%) of the title compound as a colourless solid. m.p.167-170° C.

3.2,3-Dimethyl-8-phenyl-3,6,7,8tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Amide

To a suspension of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 11.1ml (5.6 mmol) Ammonia (0.5 M in dioxane) were added and the mixture wasstirred for 24 h at room temperature. The precipitate was filtered offand dried in vacuo at 40° C. to afford 0.15 g (48%) of the titlecompound as a yellow solid. m.p. 264°-267° C.

4.2,3-Dimethyl-8-phenyl-4,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Methylamide

To a suspension of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 1.2ml (3.7 mmol) Methylamine (2 M in THF) were added and the mixture wasstirred for 24 h at room temperature. The reaction was poured into waterand the precipitate filtered off. After drying of the residue in vacuoat 40° C., 35 mg (11%) of the tile compound were isolated as a yellowsolid. m.p. 291°-292° C.

5. 2,3Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid (2-Hydroxy-ethyl)-amide

To a suspension of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 284μl (4.7 mmol) Ethanolamine were added and the mixture was stirred for 24h at room temperature. The reaction was poured into water and theprecipitate filtered off. The residue was purified by chromatography onsilica gel (dichloromethane/methanol=15:1) to afford 53 mg (17%) of thetitle compound as a yellow solid. m.p. 228°-229° C.

6.2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid (2-Methoxy-ethyl)amide

To a suspension of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 409μl (4.7 mmol) 2-Methoxy-ethylamine were added and the mixture wasstirred for 24 h at room temperature. The reaction was poured into waterand the precipitate filtered off. After drying of the residue in vacuoat 40° C., 91 mg (29%) of the title compound were isolated as a yellowsolid. m.p. 254°-256° C.

7.1-(2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)-1-morpholin-4-yl-methanone

To a suspension of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazo-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 410μl (4.7 mmol) Morpholine were added and the mixture was stirred for 24 hat room temperature. The reaction was poured into water and theprecipitate filtered off. After drying of the residue in vacuo at 40°C., 0.1 g (33%) of the title compound were isolated as a yellow solid.m.p. 291°-293° C.

8.1-(2,3-Dimethylphenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)-pyrrolidin-1-yl-methanone

To a suspension of 0.3 g (0.93 mmol)2,3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8d]imidazole-5-carboxylicacid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred for 64 h at room temperature. 392μl (4.7 mmol) Pyrrolidine were added and the mixture was stirred for 24h at room temperature. The reaction was poured into water and theprecipitate filtered off. After drying of the residue in vacuo at 40°C., 87 mg (28%) of the time compound were isolated as a yellow solid.m.p. 225°-227° C.

9.2-Isopropyl-3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

11.6 ml Phosphoric acid (85%) and 1.2 g (3.0 mmol)2-isopropyl-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methyl-3H-benzoimidazole-5-carboxylicacid dimethylamide were heated at 80° C for 90 min. After cooling toroom temperature the reaction mixture was poured into ice-water,neutralized with 6 N sodium hydroxide solution and extracted with ethylacetate. The organic layers were dried over magnesium sulphate andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (dichloromethane/methanol=50:1) to afford 0.4 g (40%) of thetitle compound as a yellow solid.

m.p. 179°-180° C.

10.2-Cyclopropyl-3-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

50 ml Phosphoric acid (85%) and 6.7 g (17.6 mmol)2-cyclopropyl-7-hydroxy-6-(3-hydroxy-3phenyl-propyl)-3-methyl-3H-benzoimidazol-5-carboxolicacid dimethylamide were heated at 80° C. for 90 min. After cooling toroom temperature the reaction mixture was poured into ice-water (400ml), neutralized with 10N sodium hydroxide solution and extracted withethyl acetate (4×300 ml). The organic layers were dried over magnesiumsulphate and concentrated in vacuo. The residue was purified bychromatography on silica gel (dichloromethane/methanol=100:1) andcrystallized from diisopropyl ether to afford 4.5 g (71%) of the titlecompound as a white solid. m. p. 176°-179° C.

11.5-Methoxymethyl-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazoleOxalic Acid

0.25 g (0.75 mmol)(2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)-methanolwere suspended in dichloromethane (10 ml) and 810 μl (1.12 mmol) thionylchloride were added dropwise. The reaction was stirred at roomtemperature for 16 h and then concentrated in vacuo. The residue wastreated with 1.5 ml (1.5 mmol) sodium methoxide solution (30% inmethanol), the mixture transferred in a sealed vessel and heated bymicrowave irradiation to 100° C. for 15 min. After cooling to roomtemperature the reaction mixture was poured into water and extractedwith dichloromethane. The organic layers were dried over magnesiumsulphate and concentrated in vacuo. The residue was, at first, purifiedby flash chromato-graphy on silica gel (dichloromethane/methanol=80:1)and then treated with oxalic acid in acetone. The precipitate wasfiltered off and washed with acetone to afford 132 mg (43%) of the titlecompound as a white solid. m.p. 204°-205° C.

12.5-(2-Methoxy-ethoxymethyl)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]-imidazoleOxalic Acid

0.23 g (0.75 mmol)(2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5yl)-methanolwere suspended in dichloromethane (10 ml) and 810 μl (1.12 mmol) thionylchloride were added dropwise. The reaction was stirred at roomtemperature for 16 h and then concentrated in vacuo. The residue wastreated with 7.5 ml (1.5 mmol) sodium 2-methoxy-ethoxide solution (1 Min 2-methoxyethanol) and the mixture stirred at room temperature for 3h. The solution was poured into water and extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo. The residue was, at first, purified by flashchromatography on silica gel (dichloromethane/methanol=20:1) and thentreated with oxalic acid in acetone. The precipitate was filtered offand washed with acetone to afford 107 mg (31%) of the title compound asa beige solid. m.p. 131°-133° C.

13.1-Aziridin-1-yl-(2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno7,8-d]imidazol-5-yl)-methanone

To a suspension of 260 mg (0.81 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]-imidazole-5-carboxylicacid in tetrahydrofuran (10 ml) were added 157 mg (1.0 mmol)N,N′-carbonyl-diimidazole (CDI) and the reaction was stirred at roomtemperature overnight 105 mg (2.4 mmol) Aziridine were added and themixture was stirred for 16 h at room temperature. The reaction waspoured into water and extracted with dichloromethane. The organic layerswere dried over magnesium sulphate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(dichloromethane/methanol=20:1) and crystallized from n-butanol toafford 56 mg (20%) of the title compound as a white solid. m.p.201°-204° C.

14.3-Methyl-8-phenyl-2-trifluoromethyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

17 ml Phosphoric acid (85%) and 1.7 g (4.0 mmol)hydroxy-(hydroxy-phenyl-propyl)-3-methyl-2-trifluoromethyl-3H-benzoimidazole-5-carboxylicacid dimethylamide were heated at 80° C. for 3 h. After cooling to roomtemperature the reaction mixture was poured into ice-water, neutralizedwith 10 N sodium hydroxide solution and extracted with dichloromethane.The organic layers were dried over magnesium sulphate and concentratedin vacuo. The residue was purified by flash chromatography on silica gel(ethyl acetate) and crystallized from diisopropyl ether to afford 210 mg(13%) of the title compound as a white solid. m. p. 223°-225° C.

15.2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Ethyl Ester

42 ml Phosphoric acid (85%) and 4.2 g (11.4 mmol)7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-di-methyl-3H-benzoimidazole-5-carboxylicacid ethyl ester were heated at 80° C. for 2 h. After cooling to roomtemperature the reaction mixture was poured into ice-water andneutralized with 10 N sodium hydroxide solution. The precipitate wasfiltered off and dried in vacuo at 40° C. to afford 3.4 g (86%) of thetitle compound as a white solid. m. p. 172°-173° C.

16.2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid

To a suspension of 3.4 g (9.6 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid ethyl ester in 100 ml dioxane and 25 ml water were added 1.4 g(57.7 mmol) lithium hydroxide and the reaction refluxed for 6 h. Aftercooling to room temperature, the reaction mixture was adjusted to pH=5with 2 M HCl solution. The precipitate was filtered off and crystallizedwith n-butanol to afford 3.0 g (96%) of the title compound as a beigesolid of m.p. 323°-326° C.

17.(2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)methanol

A solution of 250 mg (0.7 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid ethyl ester in 10 ml tetrahydrofuran was cooled to 0° C. and 927 μl(0.93 mmol) lithium aluminium hydride solution (1 M in THF) were addeddropwise. The temperature was raised to room temperature and thereaction stirred for 1 h. To the reaction were cautiously added 1.5 mlwater and 1.5 ml 6 M sodium hydroxide solution and the mixture wasextracted with dichloromethane. The organic layers were dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (toluene/dioxane=1:1) andcrystallized with diisopropyl ether to afford 101 mg (45%) of the titlecompound as a beige solid. m.p. 279°-281° C.

18.1-Azetidin-1-yl-1-(2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)-methanone

To a suspension of 0.31 g (0.96 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (10 ml) were added 0.34 g (1.4 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was heated at 40° C. for 4 h. 102 mg (1.0mmol) Azetidine were added and the mixture was stirred for 3 h. Thereaction mixture was poured into water and the extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo. The residue was purified by columnchromatography on silica gel (toluene/dioxane=1:5) and crystallized withdiisopropyl ether to afford 212 mg (61%) of the title compound as awhite solid. m.p. 246°-248° C.

19.2,3Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Propyl-amide

To a solution of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid and 0.3 g (0.93 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol)triethylamine and 76 μl (0.93 mmol) propylamine and the suspension wasstirred overnight at room temperature. The reaction was poured intowater, the precipitate filtered off and purified by columnchromatography on silica gel (dichloromethane/methanol=50:1) to afford154 mg (46%) of the toe compound as a white powder.

m.p. 273° C.

20.1-(2,3-Dimethyl-8-phenyl-3,6,7,8tetrahydro-chromeno[7,8-d]imidazolyl5-yl)-1-3-hydroxy-pyrrolidin-1-yl)methanone

To a solution of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid and 0.3 g (0.93 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol)triethylamine and 77 μl (0.93 mmol) 3-pyrrolidinol and the suspensionwas stirred overnight at room temperature. The reaction was poured intowater and the precipitate filtered off. The filtrate was neutralizedwith saturated sodium bicarbonate solution and extracted withdichloromethane (3×). The organic layers were dried over magnesiumsulphate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/methanol=100:1) to afford120 mg (33%) of the title compound as a white powder. m.p. 322°-324° C.

21.2,3-Dimethyl-8-phenyl-3,6,7,8tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid (2,3-Dihydroxy-propyl)amide

To a solution of 0.3 g (0.93 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid and 0.3 g (0.93 mmol)O(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoro-borate(TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol)triethylamine and 71 μl (0.93 mmol) 3-amino-propane-1,2-diol and thesuspension was stirred overnight at room temperature. The reaction waspoured into water, the precipitate filtered off and purified by columnchromatography on silica gel (dichloromethane/methanol=8:1) to afford100 mg (270%) of the tifle compound as a white solid.

m.p. 268°-270° C.

22.3Methoxymethyl-2-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

A suspension of 0.20 g (0.6 mmol)7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methoxymethyl-2-methyl-3H-benzoimidazole-5-carboxylicacid dimethylamide in 2 ml 85% ortho-phosphorlc acid was heated to 80°C. After 90 min stirring, the reaction was cooled to room temperature,poured into ice/water and neutralized with 10M sodium hydroxide. Thewater layer was extracted with dichloromethane, the organic layers weredried over magnesium sulphate and concentrated in vacuo. The residue wascrystallized from ethyl acetate/petroleum ether to afford 130 mg (59%)of the title compound as a beige powder. m.p. 213°-215° C.

23.N-(2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazol-5-yl)-N-methyl-acetamide

A suspension of 0.75 g (2.0 mmol)N-(7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzoimidazol-5-yl]-N-methyl-acetamidein 8 ml 85% orthcphosphodc acid was heated to 80° C. After 2 h stirring,the reaction was cooled to room temperature, neutralized with 6M sodiumhydroxide and extracted with ethyl acetate (3×20 ml). The organic layerswere dried over magnesium sulphate and concentrated in vacuo. Theresidue was crystallized from ethyl acetate/disopropyl ether (1:10) toafford the title compound (57%) as a beige soid. m.p. 214°-216° C.

24.2-Ethyl-3-methyl-4-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

A suspension of 1.3 g (3.4 mmol)2-ethyl-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methyl-3H-benzoimidazole-5-carboxylicacid dimethylamide in 13 ml 85% orthophosphoric acid was heated to 80°C. After 2 h stirring, the reaction was cooled to room temperature,neutralized with 6M sodium hydroxide (65 ml) and extracted withdichloromethane (4×150 ml). The organic layers were dried over magnesiumsulphate and concentrated in vacuo to afford 0.7 g (57%) of the titlecompound as a white solid. m.p. 195°-197° C.

25. Ethyl2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylate

To a solution of 5.0 g (14 mmol)5bromo-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]-quinolinein 71 ml ethanol and 12 ml triethylamine were added 0.47 g (2.1 mmol)palladium(II) acetate and 1.8 g (6.9 mmol) triphenylphosphine. Themixture was transferred to an autoclave and carbonylated (6 bar carbonmonoxide pressure, 100° C.) for 18 h. The reaction mixture was cooleddown, poured into water and extracted with dichloromethane. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (dichloromethane/methanol=13:1). Crystallization from ethylacetate/light petroleum ether yielded 3.22 g (66%) of the title compoundas a colourless solid. m.p. 185-186° C.

26.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicAcid

A suspension of 12 g (3.4 mmol) ethyl2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylatein 20 ml dioxane and 12 ml 2N aqueous sodium hydroxide was heated to100° C. until no starting material was left. The mixture was cooled downand neutralized with 2N hydrochloric acid. The precipitate wascollected, washed with water and dried. The crude product wasrecrystallized from ethanol to yield 0.97 g (88%) of the title compoundas a colourless solid. m.p. 325-326° C.

27.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylicAcid 2-Hydroxyethylamide

A suspension of 1.0 g (2.9 mmol) ethyl2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]-quinoline-5-carboxylatein 10 ml 2-aminoethanol was heated to 140-150° C. until no startingmaterial was left. The mixture was partitioned between saturated aqueousammonium chloride and dichloro-methane/methanol 9:1. The organic layerwas separated, dried over anhydrous magnesium sulphate and evaporated.The residue was purified by column chromatography on silica gel(toluene/dioxane/methanol=6:3:1). Crystallization from diisopropyl etheryielded 0.55 g (52%) of the title compound as a colourless solid. m.p.248-251° C.

28.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicAcid Amide

To a suspension of 0.9 g (2.8 mmol)2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylicacid in 10 ml tetrahydrofuran and 8 ml N,N-dimethylformamide were added0.5 g (3.1 mmol) N,N′-carbonyldiimidazole. After 4 h at 60° C., thesolution was cooled down and ammonia was bubbled through the flask for 4h. The mixture was allowed to stand 60 h and then poured into 100 mlwater. The precipitate was collected, washed with water and dried at 50°C. to yield 0.64 g (71%) of the title compound. m.p. 311-319° C.

29.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicAcid Methylamide

To a suspension of 1.0 g (3.1 mmol)2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicacid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added1.0 g (6.2 mmol) N,N′-carbonyldiimidazole. After 1 h at 60° C., thesolution was cooled down and 15.6 ml (31.2 mmol) methylamine (2M intetrahydrofuran) were added. The mixture was stirred 2 h at ambienttemperature and then poured into 50 ml water. The precipitate wascollected, washed with water and dried at 50° C. to yield 0.87 g (84%)of the title compound. m.p. 259° C.

30.2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicAcid 1-aziridinylamide

To a suspension of 0.47 g (1.5 mmol)2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylicacid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added0.4 g (2.5 mmol) N,N′-carbonyldiimidazole. After 1 h at 60° C., thesolution was cooled down and 0.8 g (18.6 mmol) aziridine were added in 4portions over a period of 3 h. After complete reaction, the organiclayer was separated, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (ethyl acetate/light petroleum ether=7:3). Crystallization fromdiethyl ether/n-heptane yielded 0.23 g (46%) of the title compound as acolourless solid. m.p. 192-193° C.

31.5-Hydroxymethyl-2,3-dimethyl-8-phenyl-6,7,8,9tetrahydro-3H-imidazo[4,5-h]quinoline

To a suspension of 0.2 g (5.3 mmol) lithium aluminium hydride in 15 mltetrahydrofuran was slowly added a solution of 1.0 g (2.9 mmol) ethyl2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylatein 5 ml tetrahydrofuran. After 2 h, the reaction mixture was carefullyhydrolyzed with 0.1 ml water, 0.2 ml 6N aqueous potassium hydroxide and0.1 ml water. Anhydrous magnesium sulfate was added and the mixture wasstirred 1 h. After filtration through celite, the filtrate wasevaporated and the residue purified by column chromatography on silicagel (dichloromethane/methanol=13:1). Crystallization from acetoneyielded 0.28 g (32%) of the title compound as a colourness solid. m.p.253-254° C.

32. (8S)- and(8R)-2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylicAcid Methylamide

Resolution of racemic2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5carboxylicAcid Methylamide was achieved by preparative chromatography using a250×110 mm CHIRALCEL® OD 20 μm column. The mobile phase consisted of100% acetonftrile. The separation was performed at room temperature witha flow rate of 500 ml/min. The products were detected at a wavelength of310 nm. The separation afforded 0.78 g(8S)-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicacid methylamide (ee>99.9%, m.p. 273-275° C.) and 0.79 g(8R)-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylicacid methylamide (ee 98.9%, m.p. 272-273° C.), both as colourlesssolids. The optical purity was examined by means of optical rotation.For the (8S)-enantiomer [a]^(D) ₂₀=−42 (c=0.1, dichloromethane) wasdetermined.

33.(8S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

Resolution of racemic2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid dimethylamide (0.5 g, 1.4 mmol) was achieved by preparativechromatography using a 275×110 mm CHIRALPAK® AS-V 20 μm column. Themobile phase consisted of a n-heptan/ethanol/diethylamine mixture[95/5/0.1 (v/v/v)]. The separation was performed at room temperaturewith a flow rate of 1 ml/min. The products were detected at a wavelengthof 225 nm. The separation afforded 0.19 g (39%; ee 98.9%) of the titlecompound ((8S)-enantiomer) as a white solid. m.p. 227°-228° C.

The optical purity was examined by means of optical rotation. For thetitle compound ((8S)-enantiomer) an [a]^(D) _(m) value of −89° (c=0.1,dichloromethane) was determined.

34.(8R)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

Resolution of racemic2,3-dimethylphenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid dimethylamide (0.5 g, 1.4 mmol) was achieved by preparativechromatography using a 275×110 mm CHIRALPAK® AS-V 20 μm column. Themobile phase consisted of a n-heptan/ethanol/diethylamine mixture[95/5/0.1 (v/v/v)]. The separation was performed at room temperaturewith a flow rate of 1 ml/min. The products were detected at a wavelengthof 225 nm. The separation afforded 0.19 g (39%; ee 99.8%) of the titlecompound ((8R)-enantiomer) as a white solid. m.p. 227°-228° C.

The optical purity was examined by means of optical rotation. For thetitle compound ((8R)-enantiomer) an [a]^(D) ₂₀ value of +94° (c=0.1,dichloromethane) was determined.

35.2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Cyclopropylamide

To a suspension of 0.5 g (1.5 mmol)2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid in dichloromethane (15 ml) were added 0.75 g (2.3 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the suspension was stirred overnight at room temperature. 430μl (6.2 mmol) Cyclopropylamine were added and the mixture was stirred atroom temperature for 1 h. The reaction mixture was poured into water (30ml) and extracted with dichloro-methane (3×20 ml). The organic layerswere dried over magnesium sulphate and concentrated in vacuo. Theresidue was crystallized from ethanol to afford 345 mg (62%) of thetitle compound as a white solid.

m.p. 312°-313° C.

36. 2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole

A suspension of 5 ml phosphoric acid (85%) and 260 mg (0.9 mmol)1,2-dimethyl-5-(3phenyl-allyl)-1H-benzimidazol-4-ol was heated at 90° C.for 90 min. After cooling to room temperature, the reaction mixture waspoured into water (400 ml), neutralized with 6N sodium hydroxidesolution and extracted with dichloromethane (4×300 ml). The organiclayers were dried over magnesium sulphate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(toluene/dioxane=2:1) to afford 24.5 mg (10%) of the title compound as awhite solid. m. p. 161°-164° C.

37.2-Methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide

A suspension of 0.69 g (1.4 mmol)7-hydroxy-6-(2-hydroxy-3-phenyl-propyl)-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylicacid dimethylamide and 7 ml phosphoric acid (85%) was heated at 80° C.for 1 h. After cooling to room temperature, the reaction mixture waspoured into water and neutralized with 6N sodium hydroxide solution. Theprecipitate was filtered off and purified by column chromatography onsilica gel (dichloromethane/methanol=10:1) to afford 0.34 g (72%) of thetitle compound as a yellow foam.

38.(S)-2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid Dimethylamide (314853)

A solution of 0.4 g (1.1 mmol)7-hydroxy-((R)-3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzimidazole-5-carboxylicacid dimethylamide in 20 ml dry tetrahydrofurane was treated with 0.66 g(3.3 mmol) DIAD and 0.82 g (3.2 mmol) triphenylphosphine and thereaction mixture was stirred at room temperature for 1 h. The reactionwas poured into a satured ammonium chloride solution (10 ml) andextracted with ethyl acetate. The organic layers were dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (ethyl acetate/methanol=20:1) toafford 0.15 g (42%) of the tWe compound as a white sorid. m.p. 229°-231°C. [α]_(D)=−47° (c=0.2 ln CHCl₃). The optical purity was determined bychiral HPLC: column: CHIRALPAK® AD-H 250×4.6 mm, 5 μm; solvent:ethanol/ethanol=1:1 (v/v)+0.1% diethylamine, flow rate: 1 ml/min.

The (8S)-enantiomer (99.31 area,) and the (8R)-enantiomer (0.55 area %)were eluted at retention times of 3.91 min and 4.06 min, respectively.

Starting Compounds and Intermediates

A. 2-Benzyloxy-4-bromo-6-nitro-phenylamine

To a suspension of 50 g (325 mmol) 2-amino-nitrophenol, 45 g (325 mmol)potassium carbonate and 2 g (13 mmol) sodium iodide in 400 ml ethanolwere added 47 ml (408 mmol) benzyl chloride and the mixture was heatedto 80° C. After 2 h, the reaction mixture was cooled down and thesolvent was evaporated. The residue was dissolved in ethyl acetate andextracted with water. The organic layer was dried over anhydrousmagnesium sulphate and evaporated. Coevaporation with dichloromethane(three times) led to a dark brown oily residue which was dissolved in400 ml acetonitrile. After addition of 63.4 g (356 mmol)N-bromosuccinimide, the reaction mixture was refluxed for 1 h. Aftercooling down, 400 g silica gel were added and the mixture was evaporatedto dryness. The resulting solid was put on a column and the product waseluted with ethyl acetate/light petroleum ether (4:1). Evaporation ofthe eluent afforded a solid which was recrystallized from ethylacetate/heptane to give 62 g (59%) of the title compound as a red solid.m.p. 90° C.

B. N-Acetyl-N-(2-benzyloxy-4-bromo-nitro-phenyl)acetamide

A suspension of 20 g (62 mmol) 2-benzyloxy-4-bromo-6-nitrophenylamine in120 ml acetic anhydride and 2 ml methanesulphonic add was heated to 120°C. After complete reaction (15 min), excess acetic anhydride wasevaporated in vacuo. The residue was dissolved in dichloromethane/waterand neutralized with 6N aqueous sodium hydroxide. The organic layer wasseparated, dried over anhydrous magnesium sulphate and evaporated.Crystallization of the residue from ethyl acetate/n-heptane yielded 23.2g (92%) of the title compound as a cream-coloured solid. m.p. 148° C.

C. N-(2-Amino-6-benzyloxy-4-bromo-phenyl)acetamide

A suspension of 23 g (56 mmol)N-acetyl-N-(2-benzyloxy4-bromo-6-nitro-phenyl)-acetamide, 5.5 g (34mmol) iron(III) chloride and 13.8 g activated charcoal in 600 mlmethanol was heated to reflux. To the reaction mixture were added 28 mlhydrazine hydrate (95%) to maintain gentie reflux. After completereaction (2 h), the reaction mixture was cooled down and filteredthrough celite. The filter cake was washed thoroughly withdichloromethane/methanol and the filtrate was evaporated to dryness. Theresidue was partitioned between dichloromethane/methanol and water. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulphate and evaporated. The residue was recrystallized from boilingethyl acetate/n-heptane to give 12.3 g (65%) of the title compound as acolourless solid. m.p. 185° C.

D. N-(2-Benzyloxy-4-bromo-6-dimethylamino-phenyl)acetamide

A suspension of 5 g (15 mmol)N-(2-amino-6-benzyloxy-4-bromo-phenyl)-acetamide in 80 ml methanol and34 ml formaldehyde (37%) was acidified with saturated methanolichydrogen chloride to give a clear yellow solution. To the solution wereadded 1.5 g (24 mmol) sodium cyanoborohydride in small portions. Aftercomplete reaction (15 min), the mixture was neutralized with aqueoussodium hydrogen carbonate and extracted with dichloromethane. Theorganic layer was dried over anhydrous magnesium sulphate andevaporated. Crystallization of the residue from ethyl acetate/heptaneyielded 4.3 g (79%) of the titie compound as a coloudess solid. m.p.177° C.

E-4-Benzyloxy-6bromo-1,2-dimethyl-1H-benzimidazole

A suspension of 26.2 g (72 mmol)N-(2-benzyloxy-4-bromo-6-dimethylamino-phenyl)-acetamide in 180 mlphosphoryl chloride was heated to 70° C. for 24 h. The excess ofphosphoryl chloride was evaporated in vacuo. The residue was suspendedin dichloromethane and carefully neutralized with 6N aqueous potassiumhydroxide and water. The organic layer was separated, dried overanhydrous magnesium sulphate and evaporated. Crystallization of theresidue from ethyl acetate yielded 15.1 g (63%) of the title compound asa colourless solid. m.p. 177-179° C.

F. 7-Benzyloxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic AcidDimethylamide

To a solution of 3 g (9.1 mmol)4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzimidazole in 100 mldimethylamine (3.2M solution in tetrahydrofuran) were added 0.3 g (1.3mmol) palladium(II) acetate and 1.4 g (5.3 mmol) triphenylphosphine. Themixture was transferred to an autoclave and carbonylated (6 bar carbonmonoxide pressure, 120° C.) for 16 h. The reaction mixture was cooleddown, evaporated and the residue was dissolved in dichloromethane. Theorganic layer was extracted with water, dried over anhydrous magnesiumsulphate and evaporated. Purification of the residue by columnchromatography on silica gel using ethyl acetate yielded 2.3 g (78%) ofthe title compound as a colourless solid m.p. 159-160° C.

G. 7-Hydroxy-2,3-dimethyl-3H-benzoimidazole-carboxylic AcidDimethylamide

A solution of 2.3 g (7.1 mmol)7-Benzyloxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic aciddimethyl-amide in 80 ml methanol was hydrogenated over 0.3 g 10% Pd/C (1bar H for 16 h. The catalyst was filtered off and the filtrate wasevaporated. The residue was crystallized from acetone to give 1.2 g(71%) of the title compound as a colourless solid. m.p. 248° C.

H.6-Dimethylaminomethyl-7-hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

To a suspension of 2.0 g (8.6 mmol)7-Hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic acid dimethylamidein dichloromethane (80 ml) was added dropwise a suspension of 1.7 g (9.4mmol) Eschenmoser's salt in dichloromethane (50 ml). After stirring for3 h at room temperature, the reaction mixture was poured into saturatedsodium bicarbonate solution (100 ml) and extracted with dichloromethane(2×50 ml). The organic layers were dried over magnesium sulphate andconcentrated in vacuo to give 20 g (82%) of the title compound as anorange foam. The compound was used for the next step without furtherpurification.

¹H-NMR (200 MHz; DMSO): δ=2.31 (s, 3H, Me), 2.58 (2s, 6H, 2 NCH ₃), 2.78(s, 3H, NCH ₃), 3.02 (s, 3H, NCH ₃), 3.62 (m, 5H, CH ₃N, NCH ₃), 7.79(s, 1 H, ArH).

I.7-Hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

2.0 g (6.9 mmol)6-dimethylaminomethyl-7-hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylicacid dimethylamide and 1.8 g (10.3 mmol) 1-(1-phenyl-vinyl)-pyrrolidinewere suspended in toluene (40 ml) and the reaction was refluxed overnight. After cooling to room temperature, the solvent was concentratedin vacuo. The residue was purified by column chromatography on silicagel (dichloromethane/methanol, 14:1). Crystallization from ethyl acetateafforded 1.1 g (42%) of the title compound as a beige solid. m. p.223°-224° C.

J.7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

To a suspension of 1.0 g (2.7 mmol)7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzo-imidazole-5-carboxylicacid dimethylamide in ethanol (10 ml) were cautiously added 124 mg (3.3mmol) sodium borohydride (exothermic reaction 1) and the reaction wasstirred for 2 h at room temperature. The reaction mixture was pouredinto saturated ammonium chloride solution (20 ml) and diluted with water(80 ml). The precipitate was filtered off and dried in vacuo to afford880 mg (89%) of the title compound as a beige solid. m. p. 257°-260° C.

K. 6-Bromo-2-methyl-4-nitro-1(3)H-benzimidazole

To a suspension of 65 g (0.28 mol) 4bromo-6-nitro-1,2-phenylenediaminein 600 ml ethanol were added 140 ml 5N hydrochloric acid. The reactionmixture was refluxed and 58 ml (0.56 mol) of 2,4-pentanedione were addedin one portion. After 1 h, the mixture was cooled down, poured into 500ml water and neutralized with conc. ammonia. The precipitate wascollected, washed thoroughly with water and dried over phosphoruspentoxide to give 70.8 g (99%) of the titie compound as a white solid.

M.p. 229-231° C.

L. 6-Bromo-1,2-dimethyl-4-nitro-1H-benzimidazole

To a suspension of 4.3 g (107 mmol) sodium hydride (60% w/w dispersionin mineral oil) in 25 ml N,N-dimethylformamide was slowly added asolution of 25 g (98 mmol) 6bromo-2-methyl-nitro-1(3)H-benzimidazole in100 ml N,N-dimethylformamide at 0° C. After 30 min at 0° C., 15.2 g (107mmol) methyliodide were added over 20 min. When the reaction wasfinished (45 min), 200 ml water were carefully added and the mixture wasstirred for 1 h at room temperature. The precipitate was collected,washed thoroughly with water and dried over phosphorus pentoxide invacuo. Recrystallization from methanol yielded 19.6 g (74%) of the titlecompound as a colourless solid. m.p. 193-195° C.

M. 6-Bromo-1,2-dimethyl-1H-benzimidazol-4-ylamine

To a solution of 19 g (70 mmol)6-bromo-1,2-dimethyl-4-nitro-1H-benzimidazole in 250 ml methanol wereadded 13.7 g (84 mmol) iron(III) chloride and 6 g activated charcoal.The reaction mixture was heated to 80° C. and 17 ml hydrazine hydrate(95%) were slowly added. After refluxing for 3 h, the hot reactionmixture was filtered through celite and the precipitate was washed withmethanol and dichloromethane. The filtrate was evaporated to give asuspension, which was treated with n-heptane. The precipitate wascollected, washed with n-heptane and dried in vacuo to give 13.3 g (79%)of the title compound as a white solid. m.p. 206-209° C.

N. (6-Bromo-1,2-dimethyl-1H-benzimidazol-4-yl)-(1-phenyl-allyl)-amine

6.4 g (26.7 mmol) 6-bromo-1,2-dimethyl-1H-benzimidazol-4-ylamine, 8.5 g(80 mmol) benzaldehyde and 0.3 g p-toluenesulphonic acid monohydrate in80 ml toluene were refluxed on a Dean-Stark-trap. After completereaction, the mixture was evaporated to one third of its volume anddiluted with 50 ml tetrahydrofuran. The mixture was cooled to 0° C. and80 ml (80 mmol) vinylmagnesiumbromide (1M solution in tetrahydrofuran)were added during 45 min. After 30 min., the reaction mixture washydrolyzed with saturated ammonium chloride solution, diluted with waterand extracted with ethyl acetate. The organic phase was separated,washed with water, dried over anhydrous magnesium sulphate andevaporated. The residue was purified by column chromatography on silicagel (petroleum ether/ethyl acetate=7:3). Crystallization fromdiisopropyl ether afforded 4.2 g (44%) of the title compound as acolourless solid. m.p. 137-139° C.

O. 6-Bromo-1,2-dimethyl-5-(3-phenyl-allyl)-1H-benzimidazol-4-ylamine

A suspension of 3.8 g (10.7 mmol)(6-bromo-1,2-dimethyl-1H-benzimidazol-4-yl)-(1-phenyl-allyl)-amine and3.5 g p-toluenesulphonic acid monohydrate in 80 ml toluene was refluxedfor 26 h. The suspension was poured into a mixture of 50 ml saturatedsodium hydrogencarbonate solution and 150 ml water and extracted withethyl acetate. The organic phase was separated, dried over anhydrousmagnesium sulfphate and evaporated. The residue was purified by columnchromatography on silica gel (toluene/dioxane/methanol=6:3.8:0.2).Crystallization from diisopropyl ether gave 2.45 g (64%) of the titlecompound as a colourless solid. m.p. 186-189° C.

P.5-Bromo-2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline

A suspension of 2.0 g (5.6 mmol)6-bromo-1,2-dimethyl-5-(3-phenyl-allyl)-1H-benzimidazol-4-ylamine in 10ml phosphoric acid (85%) was heated to 130° C. for 20 min. The solutionwas poured onto crushed ice and the pH adjusted to pH=9 by the additionof 6N sodium hydroxide solution. The mixture was extracted withdichloromethane/methanol (10:1), the organic phase was separated, driedover anhydrous magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica gel(toluene/dioxane/methanol=6:3.8:02). Crystallization from diisopropylether yielded 1.7 g (84%) of the title compound as a colourless solid.m.p. 206-210° C.

Q.2,3-Dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicAcid

To a suspension of 3.3 g (9.6 mmol)2,3dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8d]imidazole-5-carboxylicacid ethyl ester in dioxane (100 ml) were added 1.4 g (57.7 mmol)lithium hydroxide in 25 ml water and the mixture was refluxed for 5 h.After cooling to room temperature, the reaction was poured into waterand the pH adjusted to pH=5 with 2 N HCl. The precipitate was filteredoff and crystallized from n-butanol to afford 3.0 g (96%) of the titlecompound as a beige solid. m.p. 323°-326° C.

R.7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 1.3 g (3.3 mmol)7-hydroxy-2-isopropyl-3-methyl-6-3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicacid dimethylamide in ethanol (10 ml) was treated with 201 mg (5.3 mmol)sodium borohydride and the reaction was stirred at room temperature for2.5 h. A saturated ammonium chloride solution was added and the reactionstirred for further 30 min. The reaction mixture was poured into water(60 ml) and extracted with dichloromethane. The organic layers weredried over magnesium sulphate and concentrated in vacuo to afford 1.2 g(92%) of the title compound as a green wax.

S.7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzimidazole-5-carboxylicAcid Ethyl Ester

A solution of 4.6 g (12.5 mmol)7-hydroxy-2,3-dimethyl-6-(3-oxo-phenylpropyl)-3H-benzimidazole-5-carboxylicacid ethyl ester in ethanol (200 ml) was treated with 570 mg (15.0 mmol)sodium borohydride and the reaction was stirred at room temperature for3 h. A saturated ammonium chloride solution was added and the reactionwas poured into water (200 ml). The precipitate was filtered off anddried in vacuo at 40° C. to afford 4.4 g (95%) of the title compound asa white solid. m.p. 193°-195° C.

T.7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 3.0 g (7.2 mmol)7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-2-trifluoromethyl-3H-benzimidazole-5-carboxylicacid dimethylamide in ethanol (100 ml) was treated with 324 mg (8.6mmol) sodium borohydride and the reaction was stirred at roomtemperature for 3 h. A saturated ammonium chloride solution was added,the reaction was poured into water (100 ml) and extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo to afford 3.0 g (98%) of the title compound asa brown foam.

U.2-Cyclopropyl-7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 1.5 g (4.0 mmol)2-cyclopropyl-7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-3H-benzoimidazole-5-carboxylicacid dimethylamide in ethanol (22 ml) was treated with 283 mg (6.3 mmol)sodium borohydride and the reaction was stirred at room temperature for3 h. A saturated ammonium chloride solution was added, the reaction waspoured into water and extracted with dichloromethane (3×100 ml). Theorganic layers were dried over magnesium sulphate and concentrated invacuo to afford 1.5 g (100%) of the title compound as a orange-brownsolid. m.p. 92+-94° C.

V.7-Hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicAcid Ethyl Ester

A suspension of 12.5 g (53.4 mmol)7-hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic acid ethyl ester indry dichloromethane (500 ml) was treated with 12.8 g (69.4 mmol)N,N-dimethylmethylenimmonium iodide and the reaction was stirred at roomtemperature for 8 h. The mixture was concentrated in vacuo and theresidue (13.8 g) was suspended in toluene (500 ml). 12.1 g (70 mmol)acetophenone pyrrolidine enamine were added and the suspension washeated at 100° C. for 6 h. After cooling to room temperature, thesolvent was removed in vacuo, the residue was dissolved indichloromethane and treated with a solution of fumaric acid in methanol.The precipitate was filtered off, dissolved in water and the pH wasadjusted to pH=7 with saturated sodium bicarbonate solution. Theprecipitate was filtered off and dried in vacuo at 40° C. to afford 8.3g (48%) of the title compound as a white solid. m.p. 205°-206° C.

W.2-Cyclopropyl-7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A suspension of 8.5 g (32.8 mmol)2-cyclopropyl-7-hydroxy-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide in dry dichloromethane (500 ml) was treated with 6.6 g(36.0 mmol) N,N-dimethylmethylenimmonium iodide and the reaction wasstirred overnight at room temperature. The reaction mixture was pouredinto saturated sodium bicarbonate solution and extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo. The residue (11.4 g) was suspended in toluene(500 ml) and 9.3 g (54.0 mmol) acetophenone pyrrolidine enamine wereadded. The suspension was heated at 100° C. for 7 h and after cooling toroom temperature, the solvent was removed in vacuo. The residue waspurified by column chromatography on silica gel(dichloromethane/methanol=30:1) to afford 6.8 g (50%) of the titlecompound as a green foam.

X.7-Hydroxy-2-isopropyl-3-methyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 3.2 g (10.5 mmol)7-hydroxy-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide in dry dichloromethane (100 ml) was treated with 2.1 g(11.5 mmol) N,N-dimethyl-methylenimmonium iodide and the reaction wasstirred at mom temperature for 3.5 h. The reaction mixture was pouredinto saturated sodium bicarbonate solution and extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo. The residue (3.4 g) was suspended in toluene(70 ml) and 2.7 g (11.5 mmol) acetophenone pyrrolidine enamine wereadded. The suspension was heated at 100° C. overnight and after coolingto room temperature, the solvent was removed in vacuo. The residue waspurified by column chromatography on silica gel(dichloromethane/methanol=96.4) to afford 1.4 g (34%) of the titlecompound as a brown foam.

Y.7-Hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-2-trifluoromethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A suspension of 6.8 g (23.7 mmol)7-hydroxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylic aciddimethylamide in dry dichloromethane (350 ml) was treated with 5.7 g(30.8 mmol) N,N-dimethyl-methylenimmonium iodide and the reaction wasstirred overnight at room temperature. The reaction mixture was pouredinto water and extracted with dichloromethane. The organic layers weredried over magnesium sulphate and concentrated in vacuo. The residue(9.0 g) was suspended in toluene (100 ml) and 6.8 g (39.1 mmol)acetophenone pyrrolidine enamine were added. The suspension was heatedat 100° C. for 5 h and after cooling to room temperature, the solventwas removed in vacuo. 3.0 g (30%) of the title compound were isolated asa brown foam.

Z. 2-Cyclopropyl-7-hydroxy-3-methyl-3H-benzimidazol-5-carboxylic AcidDimethylamide

A solution of 15.4 g (42.0 mmol)7-benzyloxy-2-cyclopropyl-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide in 200 ml ethanol and 3.6 ml acetic acid was hydrogenatedover 3.4 g 10% Pd/C in autoclave (5 bar H₂) at 50° C. for 16 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo.The residue was crystallized from diisopropyl ether to afford 10 g (92%)of the title compound as a white solid.

NMR (d6-DMSO): δ=1.05 (m, 4H), 2.22 (m, 1H), 2.98 (s, 6H, N(CH ₃)₂),3.79 (s, 3H, NCH ₃), 6.52 (s, 1H), 6.96 (s, 1H), 9.7 (broad, 1H, OH).

AA. 7-Hydroxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 9.0 g (23.8 mmol)7-benzyloxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylicacid dimethylamide and 1.2 ml acetic acid in 300 mlethanol-tetrahydrofuran (1:1) was hydrogenated over 1.1 g 10% Pd/C inautoclave (5 bar H₂) at 50° C. for 16 h. The catalyst was filtered offand the filtrate concentrated in vacuo to afford 6.9 g (100%) of thetitle compound as a white solid.

m.p. 243-244° C.

AB. 7-Hydroxy-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylic AcidDimethylamide

A solution of 3.6 g (10.3 mmol)7-benzyloxy-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide and 900 μl acetic acid in 70 ml methanol was hydrogenatedover 885 mg 10% Pd/C in autoclave (5 bar H₂) at 50° C. for 15 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo toafford 3.2 g (100%) of the thie compound as a grey wax.

AC. 7-Benzyloxy-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylic AcidDimethylamide

5.6 g (15.5 mmol)4-Benzyloxy-6-bromo-2-isopropyl-1-methyl-1H-benzimidazole, 2.4 g (3.3mmol) triphenylphosphine, 521 mg (2.3 mmol) palladium(II) acetate and78.5 ml (155 mmol) dimethylamine (2 M in THF) were transferred to anautoclave and carbonylated (6 bar CO₂) at 120° C. for 3 h. The catalystwas filtered off and the filtrate was concentrated in vacuo.Purification of the residue by column chromatography on silica gel(petroleum ether/ethyl acetate=1:5) afforded 3.8 g (70%) of the tivecompound as a yellow wax.

AD. 7-Benzyloxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

15.8 g (41.0 mmol)4-Benzyloxy-6-bromo-1-methyl-2-trifluoromethyl-1H-benzimidazole, 6.4 g(24.6 mmol) triphenylphosphine, 1.4 g (6.2 mmol) palladium(II) acetateand 205 ml (410 mmol) dimethylamine (2 M in THF) were transferred to anautoclave and carbonylated (6 bar CO₂) at 120° C. for 16 h. The catalystwas filtered off and the filtrate was concentrated in vacuo.Purification of the residue by column chromatography on silica gel(dichloromethane/methanol=50:1) afforded 9.3 g (62%) of the titlecompound as a white solid. m.p. 144°-146° C.

AE. 7-Benzyloxy-2-cyclopropyl-3-methyl-3-benzimidazole-5carboxylic AcidDimethylamide

15.1 g (42.3 mmol)4-Benzyloxy-6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole, 6.6 g (25.4mmol) triphenylphosphine, 1.4 g (6.2 mmol) palladium(II) acetate, 169 ml(338 mmol) dimethylamine (2 M in THF) in 250 ml tetrahydrofuran weretransferred to an autoclave and carbonylated (6 bar CO₂) at 120° C. for16 h. The catalyst was filtered off and the filtrate was concentrated invacuo. Purification of the residue by column chromatography on silicagel (dichloromethane/methanol=40:1) afforded 15.4 g (100%) of the titlecompound as a yellow oil.

AF. 4-Benzyloxy-6-bromo-2-isopropyl-1-methyl-1H-benzimidazole

A suspension of 12.9 g (33.1 mmol)N-(benzyloxy-bromo-dimethylamino-phenyl)-isobutyramide in 27.1 mlphosphoryl chloride was heated at 90° C. for 4 h. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane andcooled to 0° C. The pH was adjusted to pH=8 by cautiously adding 10Nsodium hydroxide solution, the organic layer was separated, dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (dichloromethane/methanol=80:1)to afford 5.7 g (48%) of the title compound as a beige solid. m.p.132°-133° C.

AG. 4-Benzyloxy-6-bromo-1-methyl-2-trifluoromethyl-1H-benzimidazole

A solution of 40 g (107.8 mmol)4-benzyloxy-6-bromo-2-trifluoromethyl-1H-benzimidazole in acetone (600ml) was treated with 44.7 g (323.4 mmol) potassium carbonate and thereaction was refluxed for 1 h. 13.4 ml Methyl iodide were added and themixture was stirred for 2 h. After cooling to room temperature, theprecipitate was filtered off and the filtrate was concentrated in vacuo.Purification of the residue by column chromatography on silica gel(petroleum ether/ethyl acetate=15:1) afforded 13.2 g (32%) of the titlecompound as a white solid. m.p. 141°-142° C.

AH. N-(Benzyloxy-bromo-dimethylamino-phenyl)isobutyramide

A suspension of 12.7 g (35 mmol)N-(2-amino-6-benzyloxy-4-bromo-phenyl)-isobutyramide in methanol (400ml) and 83 ml (1.05 Mol) formaldehyde (37% in water) was acidified withhydrogen chloride to give a clear solution. 3.3 g (52.5 mmol) Sodiumcyanoborohydride were added and the reaction was stirred at roomtemperature for 3 h. The mixture was poured into water and neutralizedwith 10 N sodium hydroxide solution. The precipitate was filtered offand dried in vacuo at 40° C. to afford 13.9 g (100%) of the tilecompound as a white powder. m.p. 197°-198° C.

AI. 4-Benzyloxy-6-bromo-2-trifluoromethyl-1H-benzimidazole

To a suspension of 26.1 g (67.4 mmol)4benzyloxy-6-bromo-2-trifluoromethyl-benzimidazol-1-ol in chloroform(260 ml) were cautiously added 19 ml (202 mmol) phosphorus tribromideand the reaction was refluxed for 4 h. After cooling to roomtemperature, the reaction mixture was poured into water (600 ml),neutralized with sodium bicarbonate solution and extracted withdichloromethane. The organic layers were dried over magnesium sulphateand concentrated in vacuo to afford 19.8 g (79%) of the title compoundas a brown oil.

AJ. N-(2-Amino-6-benzyloxy-4-bromo-phenyl)-isobutyramide

A suspension of 25.2 g (64.3 mmol)N-(2benzyloxy-4-bromo-6-nitro-phenyl)-isobutyramide, 6.3 g (38.5 mmol)iron(III) chloride and 15.7 g activated charcoal in 600 ml methanol washeated to 70° C. 31.3 ml (643 mmol). Hydrazine hydrate were addeddropwise and the reaction mixture was refluxed for 90 min. After coolingto room temperature the reaction was filtered through celite, the filtercake washed with dichloromethane/methanol and the filtrate concentratedin vacuo. The residue was dried in vacuo at 40° C. to afford 13.0 g(56%) of the title compound as a white solid. m.p. 214°-215° C.

AK. 4-Benzyloxy-6-bromo-2-trifluoromethyl-benzimidazol-1-ol

A suspension of 56.6 g (135 mmol)N-(2-benzyloxy-4-bromonitro-phenyl)-2,2,2-trifluoro-acetamide in 2 Lethanol was hydrogenated over Raney-Nickel (1 bar H₂) for 3 h. Thereaction was filtered through celite and the filtrate was concentratedin vacuo. The residue was purified by column chromatography on silicagel (petroleum ether/ethyl acetate=5:1) to afford 30.6 g (58%) of thetitle compound as a beige solid.

m.p. 211°-214° C.

AL. N-(2-Benzyloxy-6-bromo-6-nitro-phenyl)-isobutyramide

A suspension of 20 g (62 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in120 ml isobutyric anhydride and 1.9 ml (50.4 mmol) methanesulphonic acidwas heated at 120° C. for 2.5 h.. After cooling to room temperature, thereaction mixture was poured into water, neutralized with 10 N sodiumhydroxide solution and extracted with dichloromethane. The organiclayers were dried over magnesium sulphate and concentrated in vacuo. Theresidue was crystallized from diisopropyl ether to afford 1.6 g (7%) ofthe title compound as a white solid. m.p. 197°-198° C.

AM. N-(2-Benzyloxy-4-bromo-6-nitro-phenyl)-2,2,2-trifluoro-acetamide

A solution of 50 g (155 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 400ml dioxane was treated with 44 ml (310 mmol) trifluoroacetic anhydrideand transferred to an autoclave. The reaction was heated at 120° C. for3 h and after cooling to room temperature, the solvent was removed invacuo. The residue was crystallized from ethanol to afford 53.6 g (83%)of the title compound as a grey solid. m.p. 146°-147° C.

AN. 4-Benzyloxy-6-bromo-1-methoxymethyl-2-methyl-1H-benzimidazole

2.0 g (6.3 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole weresolved in dimethylformamide (10 ml) and the solution was cooled to 0° C.151 mg (6.5 mmol) sodium hydride (60%) were added in portions and thereaction was stirred for 20 min. 435 μl (6.3 mmol)1-Chloro-1-methoxy-methane were added and the reaction was stirred at 0°C. After 2 h the mixture was poured into water (200 ml) and extractedwith ethyl acetate. The organic layers were dried over magnesiumsulphate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (toluene/dioxane=6:1) to afford 0.6 g (26%)of the title compound as a yellow oil.

AO. 7-Benzyloxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

10.6 g (29.3 mmol)4-Benzyloxy-bromo-1-methoxymethyl-2-methyl-1H-benzimidazole, 4.6 g (17.6mmol) triphenylphosphine, 1.0 g (4.3 mmol) palladium(II) acetate, 148 ml(293 mmol) dimethylamine (2 M in THF) in 50 ml tetrahydrofuran weretransferred to an autoclave and carbonylated (6 bar CO₂) at 120° C. for16 h. The catalyst was filtered off and the filtrate was concentrated invacuo. The purification of the residue by column chromatography onsilica gel (dichloromethane/methanol=20:1) afforded 4.9 g (50%) of thetitle compound as a yellow oil.

AP. 7-Hydroxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 1.8 g (5.0 mmol)7-benzyloxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide and 270 μl acetic acid in 150 ml ethanol was hydrogenatedover 240 mg 10% Pd/C in autoclave (5 bar H₂) at 50° C. for 18 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo andcrystallized from ethyl acetate-petroleum ether to afford 0.8 g (62%) ofthe title compound as a white solid. m.p. 173°-183° C.

AG.6-Dimethylaminomethyl-7-hydroxy-3-methoxymethyl-1H-benzimidazole-5-carboxylicAcid Dimethylamide Hydrogen Iodide

A solution of 1.0 g (3.8 mmol)7-hydroxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide in dry dichloromethane (30 ml) was treated with 0.7 g (4.2mmol) N,N-dimethyl-methylenimmonium iodide and the reaction was stirred24 h at room temperature. The reaction mixture was poured into water andextracted with dichloromethane (3×20 ml). The organic layers were driedover magnesium sulphate and concentrated in vacuo. The residue wascrystallized from diisopropyl ether to afford 1.1 g (92%) of the titiecompound as a white solid. m.p. 146°-147° C.

AR.7-Hydroxy-3-methoxymethyl-2-methyl-6-(3-oxo-3-phenyl)-1H-benzimidazole-5-carboxylicAcid Dimethylamide

1.1 g (3.4 mmol)6-Dimethylaminomethyl-7-hydroxy-3-methoxymethyl-1H-benzimidazole-5-carboxylicacid dimethylamide hydrogen iodide were suspended in toluene (25 ml) and0.8 g (4.7 mmol) acetophenone pyrrolidine enamine were added. Thesuspension was heated at 100° C. for 4 h and after cooling to roomtemperature, the solvent was removed in vacuo. The residue was purifiedby column chromatography on silica gel (dichloromethane/methanol=30:1)and crystallized from ethyl acetate to afford 0.3 g (27%) of the titlecompound as a brown solid. m.p. 210°-213° C.

AS.7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethybenzimidazole-5-carboxylicAcid Dimethylamide

A suspension of 0.2 g (0.6 mmol)7-hydroxy-3-methoxymethyl-2-methyl-6-(3-oxo-3-phenyl)-1H-benzoimidazole-5-carboxylicacid dimethylamide in ethanol (5 ml) was treated with 30 mg (0.8 mmol)sodium borohydride and the reaction was stirred at room temperature for3 h. A saturated ammonium chloride solution was added and the reactionwas extracted with dichloromethane. The organic layers were dried overmagnesium sulphate and concentrated in vacuo. The residue afforded 0.2 g(80%) of the title compound as a brown solid. m.p. 216°-218° C.

AT. N-(7-Benzyloxy-2,3-dimethyl-3H-benzimidazol-5-yl)-acetamide

A solution of 10 g (30.2 mmol)4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzimidazole, 2.1 g (36.2 mmol)acetamide, 524 mg (0.9 mmol) xantphos, 13.7 g (42.3 mmol) cesiumcarbonate and 276 mg (0.3 mmol) Pd₂(dba)₃ in 60 ml dioxane was stirredat 100° C. for 20 h. The reaction mixture was cooled to room temperatureand poured into dichloromethane. The precipitate was filtered off andthe filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (toluene/dioxane=2:1) to afford 5.8g (62%) of thetitle compound as a white foam.

AU. N-(7-Benzyloxy-2,3-dimethyl-3H-benzimidazol-5-yl)-N-methyl-acetamide

To a suspension of 5.8 g (18.8 mmol)N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-acetamide intetrahydrofuran (200 ml) were added 1.3 ml (20.5 mmol) methyl iodide and0.74 g (20.5 mmol) sodium hydride (60%) in portions. The reaction wasstirred at room temperature for 1 h and then poured into water (100 ml)and extracted with ethyl acetate (4×50 ml). The organic layers weredried over magnesium sulphate and concentrated in vacuo. The residueafforded 6.0 g (99%) of the tide compound as ochre solid. m.p. 144°-149°C.

AV. N-(7-Hydroxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide

A solution of 3.1 g (18.9 mmol)N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide and1.2 ml acetic acid in 600 ml ethanol was hydrogenated over 1.2 g 10%.Pd/C in an autoclave (5 bar H₂) at 50° C. for 18 h. The catalyst wasfiltered off and the filtrate was concentrated in vacuo to afford 4.5 g(100%) of the title compound as a yellow solid.

¹H-NMR (d6-DMSO): δ=1.8 (s, 3H, CH₃), 2.52 (s, 3H, CH₃), 3.11 (a, 3H,CH₃), 3.68 (s, 3H, CH₃), 6.39 (s, 1H, Ar), 6.91 (s, 1H, Ar), 10.0(broad, 1H, OH).

AW.N-(6-Dimethylaminomethyl-7-hydroxy-2,3-dimethyl-3H-benzimidazol-5yl)-N-methyl-acetamide

A suspension of 4.7 g (18.9 mmol)N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide indry dichloromethane (200 ml) was treated with 4.5 g (24.6 mmol)N,N-dimethylmethylenimmonium iodide and the reaction was stirredovernight at room temperature. The reaction mixture was poured intowater, neutralized with sat. sodium bicarbonate solution and extractedwith dichloromethane (2×20 ml). The organic layers were dried overmagnesium sulphate and concentrated in vacuo. The residue afforded 2.2 g(41%) of the title compound as a white solid. m.p. 181°-184° C.

AX.N-[7-Hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazol-5-yl]-N-methyl-acetamide

2.2 g (7.6 mmol)N-(6-Dimethylaminomethyl-7-hydroxy-2,3-dimethyl-3H-benzimidazol-5-yl)-N-methyl-aceto-amidewere suspended in toluene (100 ml) and 2.6 g (15.3 mmol) acetophenonepyrrolidine enamine were added. The suspension was heated at 100° C. for8 h and after cooling to room temperature, the solvent was removed invacuo. The residue was purified by column chromatography on silica gel(dichloromethane/methanol=14:1) to afford 0.83 g (30%) of the titiecompound as a beige solid. m.p. 249°-251° C.

AY.N-[7-Hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzimidazol-5yl]-N-methyl-acetamide

A suspension of 0.8 g (2.2 mmol)N-[7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazol-5-yl]-N-methyl-acetamidein ethanol (200 ml) was treated with 100 mg (3.6 mmol) sodiumborohydride and the reaction was stirred at room temperature for 1 h. Asaturated ammonium chloride solution was added and the reaction wasextracted with ethyl acetate (3×20 ml). The organic layers were driedover magnesium sulphate and concentrated in vacuo. The residue afforded0.77 g (95%) of the title compound as a beige foam.

AZ. N-(2-Benzyloxy-4-bromo-6nitro-phenyl)-N-propionyl-proplonamide

To a suspension of 23 g (0.07 Mol) 2-benzyloxy-4-bromo-6-nitro-phenylamine in propionic anhydride (55 ml) were added 3.7 g methanesulphonicacid and the reaction was heated at 125° C. for 2 h. After cooling toroom temperature, the reaction mixture was poured into water (200 ml)and extracted with dichloromethane. The organic layers were dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby chromatography on silica gel (dichloromethane) and crystallized frompetroleum ether to afford 19 g (62%) of the title compound as a redsolid. m.p. 90°-92° C.

BA. N-(2-Amino-6-benzyloxy-4-bromo-phenyl)-propionamide

A solution of 22 g (48.5 mmol)N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-propionyl-propionamide, 4.9 g (30mmol) iron(III) chloride and 7.2 g activated charcoal in 180 ml methanolwas heated to 70° C. 23.8 ml (490 mmol) Hydrazine hydrate were addeddropwise and the reaction mixture was refluxed for 90 min. After coolingto room temperature, the reaction was filtered through celite, thefilter cake washed with dichloromethane, the filtrate reduced in volumeand poured into water. The precipitate was filtered and washed withdiethyl ether to afford 19 g (89%) of the title compound as a whitesolid.

m.p. 198°-201° C.

BB. N-(Benzyloxy-bromo-dimethylamino-phenyl)propionamide

A suspension of 17 g (48.6 mmol)N-(2-amino-6-benzyloxy-4-bromo-phenyl)propionamide in methanol (140 ml)and 116 ml (1.05 Mol) formaldehyde (37% in water) was acidified withhydrogen chloride (3.8 ml) to give a dear solution. 4.6 g (72.9 mmol)Sodium cyanoborohydride were added and the reaction was stirred at roomtemperature for 1 h. The mixture was poured into water, the precipitatewas filtered off and recrystallized from diethyl ether to afford 14.8 g(81%) of the title compound as a white solid.

m.p. 176°-177° C.

BC. 4-Benzyloxy-6-bromo-2-ethyl-1-methyl-1H-benzimidazole

A suspension of 14.8 g (39.2 mmol)N-(benzyloxy-bromo-dimethylamino-phenyl)-propionamide in 35.7 mlphosphoryl chloride was heated at 70° C. for 1 h. After cooling to roomtemperature, the reaction mixture was diluted with dichloromethane andcooled to 0° C. The pH was adjusted to pH=8 by cautiously adding 10Nsodium hydroxide solution, the organic layer was separated, dried overmagnesium sulphate and concentrated in vacuo. The residue wascrystallized from diethyl ether to afford 10.1 g (75%) of the titlecompound as a white solid. m.p. 111°-115° C.

BD. 7-Benzyloxy-2-ethyl-3-methyl-3H-benzimidazole-5-carboxylic AcidDimethylamide

10 g (29 mmol) 4-Benzyloxy-6-bromo-2-ethyl-1-methyl-1H-benzimidazole,4.6 g (17.4 mmol) triphenylphosphine, 1.0 g (4.3 mmol) palladium(II)acetate in 145 ml (290 mmol) dimethylamine (2 M in THF) were transferredto an autoclave and carbonylated (6 bar CO₂) at 120° C. for 24 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo.Purification of the residue by column chromatography on silica gel(dichloromethane/methanol=93:7) and crystallization from diethyl etherafforded 11.3 g (91%) of the title compound as white crystals. m.p.104°-108° C.

BE. 2-Ethyl-7-hydroxy-3-methyl-3H-benzimidazole-5-carboxylic AcidDimethylamide

A solution of 10.9 g (26.6 mmol)7-benzyloxy-2-ethyl-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide and 1.8 ml acetic acid in 160 ml ethanol was hydrogenatedover 1.7 g 10% Pd/C in autoclave (5 bar H₂) at 50° C. for 18 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo.The residue was crystallized from acetone to afford 7 g (91%) of thetitle compound as a white solid. m.p. 193°-199° C.

BF.6-Dimethylaminomethyl-2-ethyl-7-hydroxy-3-methyl-3H-benzimidazole-5carboxylicAcid Dimethylamide

A solution of 7.0 g (25 mmol)2-ethyl-7-hydroxy-3-methyl-3H-benzimidazole-5-carboxylic aciddimethylamide in dry dichloromethane (200 ml) was treated with 5.9 g(24.6 mmol) N,N-dimethyl-methylenimmonium iodide and the reaction wasstirred overnight at room temperature. The reaction mixture was pouredinto water, neutralized with saturated sodium bicarbonate solution andextracted with dichloromethane (3×100 ml). The organic layers were driedover magnesium sulphate and concentrated in vacuo. The residue afforded6.6 g (88%) of the title compound as a yellow powder.

m.p. 183°-185° C.

BG.2-Ethyl-7-hydroxy-6-(3-oxo-3-phenyl-propy)-3-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

6.6 g (21.6 mmol)6-Dimethylaminomethyl-2-ethyl-7-hydroxy-3-methyl-3H-benzimidazole-5-carboxylicacid dimethylamide were suspended in toluene (100 ml) and 5.7 g (15.3mmol) acetophenone pyrrolidine enamine were added. The suspension washeated at 100° C. for 2.5 h and after cooling to room temperature, thesolvent was removed in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/methanol=14:1) andcrystallized from acetone-diethyl ether to afford 1.6 g (19%) of thetitle compound as a white solid. m.p. 177°-180° C.

BH.2-Ethyl-7-hydroxy-(3-hydroxy-3-phenyl-propyl)-3-methyl-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A suspension of 1.5 g (4.0 mmol)2-ethyl-7-hydroxy-3-methyl-6-(3-oxo-3-phenyl-propyl)-3H-benzimidazole-5-carboxylicacid dimethylamide in ethanol (50 ml) was treated with 0.2 g (4.8 mmol)sodium borohydride and the reaction was stirred at room temperature for1 h. A saturated ammonium chloride solution was added and the reactionwas extracted dichloromethane (4×75 ml). The organic layers were driedover magnesium sulphate and concentrated in vacuo. The residue afforded1.2 g (80%) of the title compound as a white solid. m.p. 121°-124° C.

BI.7-Hydroxy-6-(2-hydroxy-3-phenyl-propyl)-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A suspension of 0.7 g (1.4 mmol)7-hydroxy-2-methyl-6-(3-oxo-3-phenyl-propyl)-3-(2(trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylic aciddimethylamide in 20 ml ethanol was treated with 0.7 g (1.7 mmol) sodiumborohydride and the reaction was stirred at room temperature for 1 h. Asatured ammonium chloride solution was added and the reaction wasstirred for further 30 min. The reaction mixture was poured into waterand extracted with dichloromethane (3×20 ml). The organic layers weredried over magnesium sulphate and concentrated in vacuo to afford 0.7 g(100%) of the title compound as a white foam.

BJ.7-Hydroxy-2-methyl-6-(3-oxo-3-phenyl-propyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 2.6 g (7.3 mmol)7-hydroxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzo-imidazole-5-carboxylicacid dimethylamide in 160 ml dichloromethane was treated with 1.6 g (8.8mmol) N,N-dimethylmethylenimmonium iodide and the reaction was stirredat room temperature for 2.5 h. The solvent was removed in vacuo, theresidue was suspended in 30 ml toluene and the suspension was treatedwith 0.90 g (5.7 mmol) acetophenone pyrrolidine enamine. After heatingat 100° C. for 3 h, the reaction mixture was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (ethylacetate/petroleum ether=5:1) to afford 0.71 g (20%) of the titlecompound as a beige solid. m.p. 192°-194° C.

BK.7-Hydroxy-2-methyl-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

A solution of 3.6 g (8.3 mmol)7-benzyloxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzo-imidazole-5-carboxylicacid dimethylamide in 400 ml ethanol was hydrogenated over 365 mg 10%Pd/C at room temperature for 1 h. The catalyst was filtered off and thefiltrate was concentrated in vacuo. The residue was crystallized fromdiisopropyl ether to afford 2.6 g (89%) of the title compound as a whilesolid. m.p. 150°-151° C.

BL.7-Benzyloxy-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylicAcid Dimethylamide

5.8 g (13 mmol)4-Benzyloxy-6-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole,1.3 g (5.2 mmol) triphenylphosphine, 0.4 g (1.9 mmol) palladium(II)acetate and 80 ml (160 mmol) dimethylamine (2M in THF) were transferredto an autoclave and carbonylated (6 bar CO₂) at 120° C. for 16 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo.The crystallization of the residue from diisopropyl ether afforded 3.7 g(65%) of the title compound as a white solid.

m.p. 142°-146° C.

BM.4-Benzyloxy-6-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole

18.6 g (58.6 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole and 9ml (70.3 mmol) triethyl-amine were suspended in 370 ml dichloromethaneand 13.9 ml (70.3 mmol) (2-chloromethoxy-ethyl)-trimethylsilane wereadded dropwise. The reaction was stirred at room temperature for 3 h,poured into water (400 ml) and extracted with dichloromethane (3×100ml). The organic layers were dried over magnesium sulphate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (toluene/dioxane=9:1) to afford 5.9 g (23%) of the titlecompound as a beige solid. m.p. 94°-95° C.

BN.7-Hydroxy-6-((R3)-3-hydroxy-3-phenyl-propyl-2,3-dimethyl-3H-benzimidazol-5-carboxylicAcid Dimethylamide

In a flame-dried flask filled with argon, 0.8 g (2.2 mmol)7-hydroxy-2,3-dimethyl-6-(3-oxo-3-phenylpropyl)-3H-benzoimidazole-5-carboxylicacid dimethylamide were dissolved in 130 ml dry isopropanol and degassedwith argon. 295 mg (2.2 mmol) tert-Butylate and 120 mg (5 mol-%)RuCl₂[(S)-BINAP][(S)-DAIPEN] were added and the solution was transferredto an autoclave and hydrogenated at room temperature for 18 h (40 bar).The reaction mixture was poured into a satured ammonium chloridesolution (80 ml) and extracted with ethyl acetate (3×20 ml). The organiclayers were dried over magnesium sulphate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(dichloromethane/methanol=9:1) to afford 0.4 g (50%) of the titlecompound as a green solid. m.p. 262°-264° C. [α]_(D)=+62° (c=0.2 inCHCl₃).

Commercial Utility

The compounds of the formulae 1, 1a and 2 and their pharmacologicallyacceptable salts (=active compounds according to the invention) havevaluable pharmacological properties which make them commerciallyutilizable. In particular, they exhibit marked inhibition of gastricacid secretion and an excellent gastric and intestinal protective actionin warm-blooded animals, in particular humans. In this connection, theactive compounds according to the invention are distinguished by a highselectivity of action, an advantageous duration of action, aparticularly good enteral activity, the absence of significant sideeffects and a large therapeutic range.

“Gastric and intestinal protection” in this connection is understood asmeaning the prevention and treatment of gastrointestinal diseases, inparticular of gastrointestinal inflammatory diseases and lesions (suchas, for example, gastric ulcer, peptic ulcer, including peptic ulcerbleeding, duodenal ulcer, gastritis, hyperacidic or medicament-relatedfunctional dyspepsia), which can be caused, for example, bymicroorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments(e.g. certain antiinflammatories and antirheumatics, such as NSAIDs andCOX-inhibitors), chemicals (e.g. ethanol) gastric acid or stresssituations. “Gastric and intestinal protection” is understood toinclude, according to general knowledge, gastroesophageal reflux disease(GERD), the symptoms of which include, but are not limited to, heartburnand/or acid regurgitation.

In their excellent properties, the active compounds according to theinvention surprisingly prove to be clearly superior to the compoundsknown from the prior art in various models in which the antiulcerogenicand the antisecretory properties are determined. On account of theseproperties, the active compounds according to the invention areoutstandingly suitable for use in human and veterinary medicine, wherethey are used, in particular, for the treatment and/or prophylaxis ofdisorders of the stomach and/or intestine.

A further subject of the invention are therefore the active compoundsaccording to the invention for use in the treatment and/or prophylaxisof the abovementioned diseases.

The invention likewise includes the use of the active compoundsaccording to the invention for the production of medicaments which areemployed for the treatment and/or prophylaxis of the abovementioneddiseases.

The invention furthermore includes the use of the active compoundsaccording to the invention for the treatment and/or prophylaxis of theabovementioned diseases.

A further subject of the invention are medicaments which comprise one ormore active compounds according to the invention.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the activecompounds according to the invention (=active compounds) are eitheremployed as such, or preferably in combination with suitablepharmaceutical auxiliaries or excipients in the form of tablets, coatedtablets, capsules, suppositories, patches (e.g. as TTS), emulsions,suspensions or solutions, the active compound content advantageouslybeing between 0.1 and 95% and it being possible to obtain apharmaceutical administration form exactly adapted to the activecompound and/or to the desired onset and/or duration of action (e.g. asustained-release form or an enteric form) by means of the appropriateselection of the auxiliaries and excipients.

The auxiliaries and excipients which are suitable for the desiredpharmaceutical formulations are known to the person skilled in the arton the basis of his/her expert knowledge. In addition to solvents,gel-forming agents, suppository bases, tablet auxiliaries and otheractive compound excipients, it is possible to use, for example,antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents,preservatives, solubilizers, colorants or, in particular, permeationpromoters and complexing agents (e.g. cyclodextrins).

The active compounds can be administered orally, parenterally orpercutaneously.

In general, it has proven advantageous in human medicine to administerthe active compound(s) in the case of oral administration in a dailydose of approximately 0.01 to approximately 20, preferably 0.05 to 5, inparticular 0.1 to 1.5, mg/kg of body weight, d appropriate in the formof several, preferably 1 to 4, individual doses to achieve the desiredresult. In the case of a parenteral treatment, similar or (in particularin the case of the intravenous administration of the active compounds),as a rule, lower doses can be used. The establishment of the optimaldose and manner of administration of the active compounds necessary ineach case can easily be carried out by any person skilled in the art onthe basis of his/her expert knowledge.

If the active compounds according to the invention and/or their saltsare to be used for the treatment of the abovementioned diseases, thepharmaceutical preparations can also contain one or morepharmacologically active constituents of other groups of medicaments,for example: tranquilizers (for example from the group of thebenzodiazepines, for example diazepam), spasmolytics (for example,bietamiverine or camylofine), anticholinergics (for example,oxyphencyclimine or phencarbamide), local anesthetics, (for example,tetracaine or procaine), and, if appropriate, also enzymes, vitamins oramino acids.

To be emphasized in this connection is in particular the combination ofthe active compounds according to the invention with pharmaceuticalswhich inhibit acid secretion, such as, for example, H₂ blockers (e.g.cimetidine, ranitidine), H⁺/K⁺ ATPase inhibitors (e.g. omeprazole,pantoprazole), or further with so-called peripheral anticholinergics(e.g. pirenzepine, telenzepine) and with gastrin antagonists with theaim of increasing the principal action in an additive or super-additivesense and/or of eliminating or of decreasing the side effects, orfurther the combination with antibacterially active substances (such as,for example, cephalosporins, tetracyclines, penicillins, macrolides,nitroimidazoles or alternatively bismuth salts) for the control ofHelicobacter pyiori. Suitable antibacterial co-components which may bementioned are, for example, meziocillin, ampicillin, amoxicillin,cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin,erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycinand combinations thereof (for example clarithromycin+metronidazole).

In view of their excellent gastric and intestinal protection action, theactive compounds according to the invention are suited for a tree orfixed combination with those medicaments (e.g. certainantiinflammatories and antirheumatics, such as NSAIDs), which are knownto have a certain ulcerogenic potency. In addition, the compounds offormula 1 are suited for a free or fixed combination withmotility-modifying drugs.

Pharmacology

the excellent gastric protective action and the gastric acidsecretion-inhibiting action of the compounds according to the inventioncan be demonstrated in investigations on animal experimental models. Thecompounds according to the invention investigated in the model mentionedbelow have been provided with numbers which correspond to the numbers ofthese compounds in the examples.

Testing of the Secretion-Inhibiting Action on the Perfused Rat Stomach

In Table A which follows, the influence of the compounds according tothe invention on the pentagastrin-stimulated acid secretion of theperfused rat stomach after intraduodenal administration in vivo isshown. TABLE A Dose (μmol/kg) Inhibition of No. i.d. acid secretion  11 >50%  2 1 >50%  4 1 >50% 10 1 >50% 18 1 >50% 29 1 >50% 32 (8S) 1 >50%33 (8S) 1 >50%Methodology

The abdomen of anesthetized rats (CD rat, rat, female, 200-250 g; 1.5g/kg l.m. urethane) was opened after trachetomy by a median upperabdominal incision and a PVC catheter was fixed transorally in theesophagus and another via the pylorus such that the ends of the tubesjust projected into the gastric lumen. The catheter leading from thepylorus led outward into the right abdominal wall through a sideopening.

After thorough rinsing (about 50-100 ml), warm (37° C.) physiologicalNaCl solution was continuously passed through the stomach (0.5 ml/min,pH 6.8-6.9; Braun-Unita 1). The pH (pH meter 632, glass electrode EA147; φ=5 mm, Metrohm) and, by titration with a freshly prepared 0.01NNaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCl weredetermined in the effluent in each case collected at an interval of 15minutes.

The gastric secretion was stimulated by continuous infusion of 1 μg/kg(=1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 min afterthe end of the operation (i.e. after determination of 2 preliminaryfractions). The substances to be tested were administeredintraduodenally in a 2.5 ml/kg liquid volume 60 min after the start ofthe continuous pentagastrin infusion.

The body temperature of the animals was kept at a constant 37.9-38° C.by infrared irradiation and heat pads (automatic, stepless control bymeans of a rectal temperature sensor).

1. A compound of formula 1,

in which R1 is hydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl,hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- ordi-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl,fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonylamino,1-4C-alkylcarbonyl-N-1-4C-alkylamino,1-4C-alkoxy-1-4C-alkylcarbonylamino or the group —CO—NR31R32, where  R31is hydrogen, hydroxyl, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkylor 1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen, 1-7C-alkyl,3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both arebonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino,piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, x isO (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue,substituted by R4, R5, R6 and R7, which is selected from the groupconsisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl,benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyland isochinolinyl, wherein  R4 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl,carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl,aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,  R5 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethylor hydroxy,  R6 is hydrogen, 1-4C-alkyl or halogen and  R7 is hydrogen,1-4C-alkyl or halogen, and wherein  aryl is phenyl or substituted phenylwith one, two or three same or different substituents from the group of1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.2. A compound of formula 1 according to claim 1, in which R1 ishydrogen, halogen, hydroxyl, 1-4C-alkyl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl,hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- ordi-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl,fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl,1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or thegroup —CO—NR31R32, where  R31 is hydrogen, hydroxyl, 1-7C-alkyl,hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen,1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where  R31and R32 together, including the nitrogen atom to which both are bonded,are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino ormorpholino group, X is O (oxygen) or NH and Ar is a mono- or bicyclicaromatic residue, substituted by R4, R5, R6 and R7, which is selectedfrom the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl,imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl,thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl,chinolinyl and isochinolinyl, wherein  R4 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl,carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl,1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl,aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,  R5 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethylor hydroxy,  R6 is hydrogen, 1-4C-alkyl or halogen and  R7 is hydrogen,1-4C-alkyl or halogen, and wherein  aryl is phenyl or substituted phenylwith one, two or three same or different substituents from the group of1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen,trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.3. A compound of formula 1 according to claim 1, in which R1 ishydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl, R2 ishydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R3 is hydrogen, halogen,carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32, where R31 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen or 1-4C-alkyl, or where  R31and R32 together, including the nitrogen atom to which both are bonded,are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino, piperidino,piperazino, N-1-4C-alkylpiperazino or morpholino group, X is O (oxygen)or NH and Ar is a phenyl group, substituted by R4, R5, R6 and R7,wherein  R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy,2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl,carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy,trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino,1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,  R5 is hydrogen,1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethylor hydroxy,  R6 is hydrogen, 1-4C-alkyl or halogen and  R7 is hydrogen,1-4C-alkyl or halogen, or a hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof.
 4. A compound according to claim 1,characterized by the formula 1a,

in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl orfluoro-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,R3 is hydrogen, halogen, carboxyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl-N-1-4C-alkylaminoor the group —CO—NR31R32, where  R31 is hydrogen, 1-4C-alkyl,3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  R32is hydrogen or 1-4C-alkyl, or where  R31 and R32 together, including thenitrogen atom to which both are bonded, are a pyrrolidino,hydroxypyrrolidino, aziridino, azetidino, piperidino, piperazino,N-1-4C-alkylpiperazino or morpholino group, R4 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl,amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 ishydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O (oxygen) or NH, or ahydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.5. A compound of formula 1a according to claim 4, in which R1 is1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R3 is hydrogen, carboxyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl-N-1-4C-alkylaminoor the group —CO—NR31R32, where  R31 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen or1-4C-alkyl, or where  R31 and R32 together, including the nitrogen atomto which both are bonded, are a pyrrolidino, aziridino, azetidino ormorpholino group, R4 is hydrogen, R5 is hydrogen and X is O (oxygen) orNH, or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof.
 6. A compound of formula 1a according to claim 4, in which R1is 1-4C-alkyl, 3-7C-cycloalkyl or fluoro-1-4C-alkyl, R2 is 1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl, R3 is carboxyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonyl-N-1-4C-alkylaminoor the group —CO—NR31R32, where  R31 is hydrogen, 1-4C-alkyl,hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen or1-4C-alkyl, or where  R31 and R32 together, including the nitrogen atomto which both are bonded, are a pyrrolidino, hydroxypyrrolidino,aziridino, azetidino or morpholino group, R4 is hydrogen, R5 is hydrogenand X is O (oxygen) or NH, or a hydrate, solvate, salt, hydrate of asalt or solvate of a salt thereof.
 7. A compound of the formula 1aaccording to claim 4, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 ishydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or the group —CO—NR31R32,where  R31 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or1-4C-alkoxy-2-4C-alkyl and  R32 is hydrogen, or where  R31 and R32together, including the nitrogen atom to which both are bonded, are apyrrolidino group, R4 is hydrogen, R5 is hydrogen and X is O (oxygen) orNH, or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof.
 8. A compound of formula 1a according to claim 4, in which R1is 1-4C-alkyl or fluoro-1-4C-alkyl, R2 is 1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl, R3 is carboxyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group —CO—NR31R32, where  R31is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyland  R32 is hydrogen or 1-4C-alkyl, or where  R31 and R32 together,including the nitrogen atom to which both are bonded, are a pyrrolidinoor morpholino group, R4 is hydrogen, R5 is hydrogen and X is O (oxygen)or NH, or a hydrate, solvate, salt, hydrate of a salt or solvate of asalt thereof.
 9. A compound according to claim 1, characterized by theformula 2,

in which R1 is 1-4C-alkyl or 3-7C-cycloalkyl, R2 is hydrogen or1-4C-alkyl, R3 is 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkyl or the group —CO—NR31R32, where  R31 is hydrogen,1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  R32 ishydrogen or 1-4C-alkyl, or where  R31 and R32 together, including thenitrogen atom to which both are bonded, are a pyrrolidino, aziridino,azetidino or morpholino group, R4 is hydrogen, R5 is hydrogen and X is O(oxygen) or NH, or a hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof.
 10. A compound of formula 2 according toclaim 9, in which R1 is 1-4C-alkyl, 3-7C-cycloalkyl orfluoro-1-4C-alkyl, R2 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R3 iscarboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl,1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,1-4C-alkylcarbonyl-N-1-4C-alkylamino or the group —CO—NR31R32, where R31is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxy-1-4C-alkyl and  R32 is hydrogen or 1-4C-alkyl, or where  R31and R32 together, including the nitrogen atom to which both are bonded,are a pyrrolidino, hydroxypyrrolidino, aziridino, azetidino ormorpholino group, R4 is hydrogen, R5 is hydrogen and X is O (oxygen) orNH, or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof.
 11. A pharmaceutical composition comprising a compound asclaimed in claim 1 and/or a pharmacologically acceptable hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof togetherwith a pharmaceutically acceptable auxiliary and/or excipient. 12.(canceled)
 13. A method of preventing or treating a gastrointestinaldisorder in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound as claimed inclaim 1 or a hydrate, solvate, salt, hydrate of a salt or solvate of asalt thereof.
 14. A compound of formula 1 according to claim 1 selectedfrom the group consisting of(8S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid dimethylamide,(8S)-2-methyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid dimethylamide oxalate, and(8S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylicacid methylamide.